WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau
PCT
INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(51) International Patent Classification 6
A61K 31/17
Al
(11) International Publication Number:
(43) International Publication Date:
WO 96/25157
22 August 1996 (22.08.96)
(21) International Application Number: PCT/US96/02260
(22) International Filing Date: 16 February 1996 (16.02.96)
(30) Priority Data:
08/390,260
17 February 1995 (17.02.95) US
(60) Parent Application or Grant
(63) Related by Continuation
US
Filed on
08/390,260 (CIP)
17 February 1995 (17.02.95)
(71) Applicant (for all designated States except US): SMITHKLINE
BEECHAM CORPORATION [US/US]; Corporate Intellec-
tual Property, UW2220, 709 Swedeland Road, P.O. Box
1539, King of Prussia, PA 19406-0939 (US).
(72) Inventors; and
(75) Inventors/Applicants (for US only): WTDDOWSON, Kather-
ine, Louisa [CA/US]; 1047 Old Valley Forge Road, King of
Prussia, PA 19406 (US). VEBER, Daniel, Frank [US/US];
290 Batleson Road, Ambler, PA 19002 (US). JUREWICZ,
Anthony, Joseph [US/US]; 523 Fruit Farm Road, Royers-
ford, PA 19468 (US). RUTLEDGE, Melvin, Clarence, Jr.
[US/US]; 2148 Schultz Road, Lansdale, PA 19446 (US).
HERTZBERG, Robert, Philip [US/US]; 121 Longnelds
Way, Downingtown, PA 19335 (US).
(74) Agents: DINNER, Dara, L. et al.; SmithKline Beecham
Corporation, Corporate Intellectual Property, UW2220, 709
Swedeland Road, P.O. Box 1539, King of Prussia, PA
19406-0939 (US).
(81) Designated States: JP, US, European patent (AT, BE, CH, DE,
DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).
Published
With international search report.
With amended claims.
(54) Title: IL-8 RECEPTOR ANTAGONISTS
(57) Abstract
This invention relates to the novel use of phenyl ureas in the treatment of disease states mediated by the chemokine, Interleukin-8
(IL-8).
FOR THE PURPOSES OF INFORMATION ONLY
Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
applications under the PCT.
AM
Armenia
GB
United Kingdom
MW
Malawi
AT
Austria
GE
Georgia
MX
Mexico
AU
Australia
GN
Guinea
NE
Niger
BB
Barbados
GR
Greece
NL
Netherlands
BE
Belgium
HU
Hungary
NO
Norway
BF
Burkina Faso
IE
Ireland
NZ
New Zealand
BG
Bulgaria
IT
Italy
PL
Poland
BJ
Benin
JP
Japan
PT
Portugal
BR
Brazil
KE
Kenya
RO
Romania
BY
Belarus
KG
Kyrgystan
RU
Russian Federation
CA
Canada
KP
Democratic People's Republic
SD
Sudan
CF
Central African Republic
of Korea
SE
Sweden
CG
Congo
KR
Republic of Korea
SG
Singapore
CH
Switzerland
KZ
Kazakhstan
SI
Slovenia
CI
Cote d'lvoire
LI
Liechtenstein
SK
Slovakia
CM
Cameroon
LK
Sri Lanka
SN
Senegal
CN
China
LR
Liberia
sz
Swaziland
CS
Czechoslovakia
LT
Lithuania
TD
Chad
CZ
Czech Republic
LU
Luxembourg
TG
Togo
DE
Germany
LV
Latvia
TJ
Tajikistan
DK
Denmark
MC
Monaco
TT
Trinidad and Tobago
EE
Estonia
MD
Republic of Moldova
UA
Ukraine
ES
Spain
MG
Madagascar
UG
Uganda
FI
Finland
ML
Mali
US
United States of America
FR
France
MN
Mongolia
UZ
Uzbekistan
GA
Gabon
MR
Mauritania
VN
Viet Nam
WO 96/25157
PCT/US96/02260
IL-8 RECEPTOR ANTAGONISTS
FIELD OF THE INVENTION
This invention relates to a novel group of phenyl urea compounds, processes lor the
preparation thereof, the use thereof in treating IL-8. GROa. GROp. GROyand NAP-2
mediated diseases and pharmaceutical compositions lor use in such therapy.
BACKGROUND OF THE INVENTION
Many different names have been applied to Interleukin-8 (IL-8). such as neutrophil
attractant/activauon protein- 1 (NAP- 1 ). monocyte derived neutrophil chemotacuc factor
(MDNCF), neutrophil activating factor (NAF). and T-cell lymphocyte chemotacuc factor
Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells It is
produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and
epithelial cells exposed to TNF, IL- 1 a, IL- 1 p or LPS. and by neutrophils themselves when
exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al. J. Clin Inv^,
84, 1045 (1989); j. Schroder etal, J, Immunol 139, 3474 (1987) and J. Immunol 144
2223 (1990) : Strieter. et al. Science ?4\ 1467 ( 1989) and J. Biol Them 264 10621
(1989); Cassatellaet al, J. Immunol J4X 32 16 (1992).
Grooc. CROP. GROyand NAP-2 also belong to the chemokine a family. Like IL-8
these chemokincs have also been referred in by different names. For instance GROa p y have
been referred to as MGSAa. p and y respectively (Melanoma Growth Stimulating Activity,
see Richmond et al. J. Cell Physiology 129. 375 (1986, and Chang e. al. J. Immnnnl 1 48 45 I
(1992). All ot the chemokines of the a-family which possess the ELR motif direcUy prcced.ni:
the CXC motif bind to the IL-8 B receptor
IL-8. Groa. GROp. GROyand NAP-2 stimulate a number of functions m vitro. Thev
have all been shown to have chcmoatiraaan. properties lor neutrophils, while IL-8 and GROa
have demonstrated T- lymphocytes, and basophils chemotacuc aciivnv. In addition IL-8 can
induce histamine release from basophils Irom both normal and atopic individuals GRO-cx and
IL-8 can in addition, induce lyso/omaJ cn/yme release and respiratory burst from neutrophils
ILr8 has also been shown 10 increase the surface expression of Mac- 1 fCDI lb/CD 18) on
neutrophils without de novo protein synthesis. This may contribute 10 increased adhesion of
the neutrophils 10 vascular endothelial cells Many known diseases arc characterized by
massive neutrophil infiltration. As IL-8. Groa, GROp. GROyand NAP-2 promote the
accumulation and activation of neutrophils, these chemokines have been implicated in a wide
range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis
Bagg.oi.n, et al. FEB§ Le U *07 . 97 (1992,; Miller et al. Crit. Rev Immnnnl n ,7 f ,09,,.
WO 96/25157
PCTAJS96/02260
Oppcnheim ct al, Annu. Rev. Immunol. 9 . 617 (1991): Seitzetal., J. Clin. Invest. 87 . 463
(1991): Miller et al Am Rev. Rcspir. Pis. 146 . 427 (1992): Donnely et al., Lancet 34 1 . 643
(1993) In addition the ELR chemokines (those containing the amino acids ELR motif just
prior to the CXC motif) have also been implicated in angioslasis. Stricter et al. Science 258,
5 1798(1992).
In vitro. IL-8, Groa, GROP, GROyand NAP-2 induce neutrophil shape change,
chemoiaxis, granule release, and respiratory burst, by binding to and activating receptors of the
seven- transmembrane. G-protein-linked family, in particular by binding to IL-8 receptors,
most notably the B-receptor. Thomas et al., J. Biol. Chem. 266 . 14839 (1991): and Holmes
10 et al., Science 253 . 1278 (1991). The development of non-peptide small molecule antagonists
for members of this receptor family has precedent. For a review see R. Freidinger in:
Progress in Drug Research . Vol. 40, pp. 33-98, Birkhauser Verlag. Basel 1993. Hence, the
IL-8 receptor represents a promising target for the development of novel anti-inflammatory
agents.
15 Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-
8Rot. which binds only IL-8 with high affinity, and IL-8RP. which has high affinity for IL-8
as well as for GRO-a. GROp, GROy and NAP-2. See Holmes et al.. supra: Murphy et al..
Science 253 . 1280 (1991): Lee et al.. J. Biol. Chem . 267. 16283 (1992): LaRosa et al., L
Biol. Chem. 267 . 25402 (1992); and Gayle et al., J Biol. Chem. 268 . 7283 (1993).
20 There remains a need for treatment, in this field, for compounds which are capable of
binding to the IL-8 a or p receptor. Therefore, conditions associated with an increase in IL-8
production (which is responsible for chemoiaxis of neutrophil and T-cclls subsets into the
inflammatory site) would benefit by compounds which arc inhibitors of IL-8 receptor binding
25 SUMMARY OF THE INVENTION
This invention provides for a method of treating a chemokinc mediated disease,
wherein the chcmokine is one which binds to an IL-8 a or P receptor and which method
comprises administering an effective amount of a compound of Formula (I) or a
pharmaceiiiically acceptable salt thereof. In particular the chcmokine is IL-8.
30 This invention also relates to a method of inhibiting the binding of IL-8 to its receptors
in a mammal in need thereof which comprises administering to said mammal an effective
amount of a compound of Formula (I).
Compounds of Formula (I) useful in the present invention arc represented by the
structure:
35
WO 96/25157
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-3-
wherein
X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
5 Rl is independently selected from hydrogen: halogen: nitro: cyano; halosubslituted C\.\o
alkyl: C mo alkyl: C2-10 alkenyl; Cj-io alkoxy; haJosubstituted C\. \q alkoxy: azide:
S(0) t R4: hydroxy; hydroxy C i -4alkyl; aryl; aryl C i .4 alkyl: aryloxy: aryl C | .4 alkyloxy:
heteroaryl: heteroarylalkyl ; heterocyclic, heterocyclic Ci-4alkyl: heteroaryl Cj-4 alkyloxy;
aryl C2- 10 alkenyl; heteroaryl C2- 10 alkenyl; heterocyclic C2- 10 alkenyl; NR4R5: C2-K)
10 alkenyl C(0)NR4Rs; C(0)NR4R5; C(O)NR4Ri0; S(0)3H; S(0)3R8: Ci-io alkyl
CCO)R l 1: C2-IO alkenyl C(0)R 1 1; C2-IO alkenyl C(0)OR \ \ ; C(0)R 1 \ ; C(0)OR 1 2 :
OC(O) R 1 1 ; NR4C(0)R 1 1 : or two R 1 moieties together may form 0(CH2) S 0- or a 5 to 6
membered unsaturated ring;
l is 0, or an integer having a value of I or 2;
15 s is an integer having a value of 1 to 3;
R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci_4alkyl, optionally substituted heteroaryl.
optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclic C | .4 alkyl. or R4
and R5 together with the nitrogen to which they arc attached form a 5 to 7 member ring
20 which may optionally comprise an additional hetcroatom selected from O/N/S:
Y is independently selected from hydrogen; halogen: nitro: cyano: halosubslituted C \. 10 alkyl:
Ci-io alkyl; C2-K) alkenyl: Cj-io alkoxy: halosubslituted C\-]() alkoxy: azide: S(0) ( R4:
hydroxy: hydroxyCi-4alkyl: aryl: aryl C1.4 alkyl: aryloxy: arylCi-4 alkyloxy: heteroaryl:
heteroarylalkyl: heteroaryl C1-4 alkyloxy; heterocyclic, heterocyclic C1.4alk.vl: aryl C2-I0
25 alkenyl: heteroaryl C2-10 alkenyl: heterocyclic C2-K) alkenyl: NR4R5: C2-K) alkenyl
C(0)NR4R 5 ; QO)NR4R5: C(0)NR4Ri(): S(0)3H: S(0)3R8: C\.\o alkyl C(0)Rn:
C2- 10 alkenyl C(0)R] 1: C2-10 alkenyl C(0)OR 1 1 : C(0)Ri 1 : C(0)ORi2: OC(O) R\ \ :
NR4C(0)Ri 1 : or two Y moieties together may form 0-(CH2)sO- or a 5 to 6 membered
unsaturated ring:
30 n is an integer having a value of 1 to 3:
m is an integer having a value of 1 to 3:
Rx is hydrogen or C 1.4 alkyl:
R|0 is Ci-io alkyl C(0)2R8:
WO 96/25157
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4 -
R| I is hydrogen, C 1-4 alkyl, optionally substituted aryl. optionally substituted aryl C ] -4alkyl.
optionally substituted heteroaryl. optionally substituted heteroarylC | -4alkyl. optionally
substituted heterocyclic, or optionally substituted heicrocyclicC ] -4alkyl;
Rl2 is hydrogen. C i-io alkyl, optionally substituted aryl or optionally substituted arylalkyl:
or a pharmaceutical^ acceptably salt thereof.
Another aspect of the present invention is to a method of treating a chemokinc mediated
disease, wherein the chemokine is one which binds to an IL-8 a or p receptor and which
method comprises administering an effective amount of a compound of Formula (II) or a
pharmaceutical^ acceptable salt thereof, as defined herein.
This invention also relates to a method of inhibiting the binding of IL-8 to us receptors
in a mammal in need thereof which comprises administering to said mammal an effective
amount of a compound of Formula (II), as defined herein.
This invention also relates to the novel compounds of Formula (II), or a
pharmaceutical^ acceptable salt thereof, as defined herein.
Another aspect of the present invention is to a method of treating a chemokine mediated
disease, wherein the chemokine is one which binds to an IL-8 a or p receptor and which
method comprises administering an effective amount of a compound of Formula (III) or a
pharmaceutically acceptable salt thereof, as defined herein.
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors
in a mammal in need thereof which comprises administering to said mammal an effective
amount of a compound of Formula (III), as defined herein.
This invention also relates to the novel compounds of Formula (III), or a
pharmaceutically acceptable salt thereof, as defined herein.
DETAILED DESCRIPTION OFTHF. INVENTION
The compounds of Formula (I) may also be used in association with the veterinary
treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines
which bind to the IL-8 a and p receptors. Chemokine mediated diseases for treatment,
therapeutically or prophylactically. in animals include disease states such as those noted herein
in the Methods of Treatment section.
In compounds of Formula (I). R is suitably any functional moiety which provides an
lomzable hydrogen having a pKa of 10 or less, preferably from about 3 to 9. more prclerablv
lrom about 3 to 7. Such functional groups include, but are not limited to. hydroxy, carboxvlic
acid, thiol. -SR2 -OR2. -NH-C(0)R a , -C(0)NR 6 R7- a substituted sulfonamides of the
formula -NHS(0) 2 R b . -S(0) 2 NHR c , NHC(X2)NHR b . or a tetrazolyl: wherein X 2 is oxygen
or sulfur, preferably oxygen. Preferably, the functional group is other than a sulfonic acid.
WO 96/25157
PCT/US96/02260
either directly or as a substituent group on the aryl. heieroaryl. or hetcrocvclic moiety ring,
such as in SR 2 or OR 2 . More preferably R is OH. SH. or NHS(0) 2 R h .' Suitably. R 2 is a
substituted aryl, heieroaryl, or heterocyclic moiety which ring has the functional moiety
providing the ionizable hydrogen having a pKa of 10 or less
Suitably, R 6 and R 7 are independently hydrogen or a C1-4 alkyl group, or R 6 and R 7
together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may
optionally contain an additional heteroatom which hetcroatom is selected from oxygen, nitrogen
or sulfur. This heteroring may be optionally substituted as def ined herein.
Suitably R a is an alkyl, aryl. arylC|- 4 alkyl, heieroaryl. hcieroarvlC|_ 4 alkyl.
heterocyclic, or a heterocyclic C | - 4 alkyl moiety, all of which may be optionally substituted, as
defined herein below.
Suitably, R b is a NR 6 R 7 , alkyl, aryl, arylC |. 4 alkyl. arylC 2 . 4 alkenyl, heieroaryl.
heteroarylCi- 4 alkyl, heieroarylC 2 . 4 alkenyl, heterocyclic, or heterocyclic C] - 4 alkyl. or a
heterocyclic C 2 . 4 alkenyl moiety, camphor, all of which may be optionally substituted one 10
three limes independently by halogen; nitro: halosubstituted C]- 4 alkyl. such as CF3: C| .4
alkyl, such as methyl; C|. 4 alkoxy. such as methoxy; NR9C(0)R a : C(0)NR6R 7 . S(0)3H. or
C(0)OCi- 4 alkyl. Rb is preferably an optionally substituted phenyl, benzyl, or styryl. When
Rb is a heieroaryl preferably it is an optionally substituted thiazolc. optionally substituted
thienyl, or optionally substituted quinolinyl ring. Wherein Ro is hydrogen or a C |. 4 alkyl.
preferably hydrogen, and suitably when the substiiucni group is NRoC(C»R a . then R a is
preferably an alkyl group, such as methyl
Suitably R c is hydrogen, alkyl. aryl. arylC 1 - 4 alkyl. arylC 1 - 4 alkcnyl. heieroaryl.
heteroarylCi_ 4 alkyl. heteroarylCi- 4 alkenyl. heterocyclic, or heterocyclic C | . 4 alkyl. or a
heierocyclic C]. 4 alkenyl moiety, all of which may be optionally substituted one to three limes
independently by halogen, nitro. halosubsututed C | .4 alkyl. C 1.4 alkyl. C|- 4 alkoxy.
NR 9 C(0)R a , C(0)NR 6 R7- S(0) 3 H, orC(0 )OC,. 4 alkyl. wherein Ro ,.s hydrogen or a C 1.4
alkyl. Preferably, R c is an optionally substituted phenyl.
When R is an OR 2 or SR 2 moiety 11 is recognized by one of skill 111 the art thai the aryl
ring must, therefore, contain the required ionizable hydrogen. The aryl ring may also be
additionally substituted, independently, by one to three groups, which groups may also contain
an additional ionizable group, and which include but are not limited to. halogen, nitro.
halosubstituted C 1 .4 alkyl. C1-4 alkyl. C 1.4 alkoxy. hydroxy. SH. -C(0)NR6R7.
-NH-C(0)R a , -NHS(0) 2 R h . S(0) 2 NR 6 R7- C(Q)OR K . or a tetrazolyi nnc.
WO 96/25157
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- 6 -
In compounds of Formula (I), .suitably R | is independently selected from hydrogen;
halogen; nitro; cyano; halosubstituted C] - 1<) alkyl. such as CF3; C i- 10 alkyl. such as methyl.
ethyl, l.sopropyl. or n-propyl; C2- 10 alkenyl; C\.\o alkoxy. such as methoxy. or ethoxy;
5 halosubstituted C ]. 10 alkoxy, such as irifluoromcihoxy: azide; S(0)tR4. wherein 1 is 0. 1 or 2:
hydroxy; hydroxy Ci-4alkyl. such as methanol or ethanol; aryl. such as phenyl or naphlhyl;
aryl Ci-4 alkyl. such as benzyl; aryloxy. such as phenoxy; aryl C1.4 alkyloxy, such as
benzyloxy; heteroaryl; heteroarylaikyl; hetcroaryl Ci .4. alkyloxy; aryl C2-10 alkenyl ;
heteroaryl C2-10 alkenyl; NR4R5; C2-K) alkenyl-C(0)NR4R5; C(0)NR4R5: C(0)NR4Rl();
1 0 S(0)3H; S(0)3R8: C l - 1 0 alkyl C(0)R l | ; C2- 10 aJkeny 1 C(0)R | ] . C.2- 1 0 alkenyl C(0)OR | 1 :
C(0)R 1 1 : C(0)OR ] 2- such as carboxy, methylcarboxylate or phenylbcnzoate: OC(O) R 1 1 ;
NR4C(0)Ri 1 ; azido; or two Ri moieiies together may form 0-(CH2)sO- or a 5 to 6
membered unsaturated ring; and s is an integer having a value of 1 10 3 The aryl, arylalkyl.
arylalkenyl. heteroaryl, heteroarylaikyl. heteroarylalkenyl, heterocyclic, hetcrocyclicalkyl. and
1 5 heterocyclicalkenyl moieiies may all be optionally substituted as defined herein below.
Preferably Ri is other than azido or S(0)3Rg.
When R | forms a dioxybridge. s is preferably 1 . When R | forms an additional
unsaturated ring, it is preferably 6 membered resulting in a naphthylenc ring system. This
20 naphthylene ring may be substituted independently, 1 to 3 times by the other R 1 moieiies as
defined above.
Suitably, R4 and R5 are independently hydrogen, optionally substituted C)-4 alkyl.
optionally substituted aryl- optionally substituted aryl Ci-4alkyl. optionally substituted
25 heteroaryl. optionally substituted hetcroaryl C 1 -4alkyl. heterocyclic. heteroeyclicC | -4 alkyl. or
R4 and R5 together with the nitrogen 10 which they are attached form a 5 10 7 member ring
which may optionally comprise an additional hetcroatom selected from O/N/S
R|0 is suitably C 1- 10 alkyl C(0)2RX- such as CH2C(OpH or CH2C(0)2CH3.
30
R] I is suitably hydrogen, C 1-4 alkyl. aryl. aryl C j-4 alkyl. heteroaryl. hetcroaryl
Ci-4alkyl. heterocyclic, or heterocyclic C|-4alkyl.
Rl2 is suitably hydrogen. C 1 - 10 alkyl. optionally substituted aivl or optionally
35 substituted arylalkyl
Preferably R 1 is halogen, cyano. nuro. CF3. C(0)NR4Rs. alkenyl C(0)NR4R;S. C(C)>
R4RK). alkenyl C(0)ORi2- heteroaryl. heteroarylaikyl . hete roaryl alkenyl. or S(0)NR4R.5-
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- 7 -
and preferably R4 and R5 are boih hydrogen or one is phenyl. A preferred ring substitution
lor R 1 is in the 4-posilion of the phenyl ring.
When R is OH. SH or NS02Rb than R] is preferably substituted in the 3-posilion. the
4- position or di substituted in the 3,4- position. The substitueni group is suitably an electron
withdrawing moiety. Preferably when R is OH, SH or NS02Rb- than R] is nitro. halogen,
eyano. trilluoromcthyl group. C(0)NR4R5.
When R is carboxylic acid, than R | is preferably hydrogen, or R 1 is preferably
subsututed in the 4-position. more preferably substituted by trifluoromethyl or chloro.
In compounds of Formula (I), suitably Y is independently selected from hydrogen:
halogen; nitro: cyano: halosubstituted C\. 10 alkyl: C mo alkyl: C2-10 alkenyl; Cmo alkoxy:
halosubstituted C|-io alkoxy: azide: S(0) t R4: hydroxy: hydroxy C1.4alk.vl: aryl; aryl C 1.4
alkyl: aryloxy: arylC] .4 alkyloxy: aryl C2- 10 alkenyl; heteroaryl: heteroarylalkyl; heteroaryl
C] .4 alkyloxy: heteroaryl C2- 10 alkenyl: heterocyclic, heterocyclic Ci-4alkyl: heterocydicC2-
10 alkenyl: NR4R5; C2- 10 alkenyl C(0)NR4R5: C(0)NR4R5: C(O)NR4R 10 ; S(0)3H:
S(0)3R8: C 1 . 1 0 alkyl C(0)R 1 1 ; C2- 1 0 alkenyl C(0)R 1 1 ; C 2 - 10 alkenyl C(0)OR 1 1 ;
C(0)R 1 1 : C(0)OR 1 2: OC(O) R 1 1 : NR 4 C(0)R 1 1 : azido: or two Y moieties together may form
0-(CH2)s0- or a 5 to 6 mcmbered unsaturated ring. When Y forms a dioxybridge, s is
preferably 1 When Y forms an additional unsaturated ring, it is preferably 6 membered
resulting in a naphthylcnc ring system. This naphthylene ring may be substituted 1 to 3 times
by other Y moieties as defined above. The aryl. heteroaryl and heterocyclic moieties noted
above may all be optionally substituted as defined herein. Preferably R | is other than azido or
S(0)3Rs
Y is preferably a halogen. C 1.4 alkoxy. optionally substituted aryl. optionally
substituted aryloxy or arylalkoxy. methylene dioxy. NR4R5. thioC1.4alk.vl. thioaryl.
halosubstituted alkoxy. optionally substituted C 1 .4 alkyl. or hydroxy alkyl. Y is more
preferably mono-substituted halogen, disubstituicd halogen, mono-substituted alkoxy.
disubstitutcd alkoxy. methylenedioxy. aryl. or alkyl. more preferably these groups are mono 01
di-subsuiuted in the 2 - position or 2'-. ^'-position.
While Y may be substituted in any of the 5 ring positions, preferably when R is OH.
SH. or NS02Rb- Y is preferably mono-substituted in the 2-position or 3 - position, with the
4 - preferably being unsubstiluted If the ring is disubstituted. when R is OH. SH. or
NS02Rb- substnuents are preferably in the 2' or 3 position of a monocyclic ring. While both
WO 96/25157
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Rl and Y can bolh be hydrogen, it is prelered thai at least one of the rings be substituted,
preferably bolh rings arc substituted.
In compounds of Formula (I), X is suitably oxygen or sulfur, preferably oxygen.
5
While not explicitly covered by Formula (I), (Ia-c). (II). or (III), another aspect of this
invention arc the symmetrical bis compounds which are included for each structure.
Compounds exemplified by this bis like structure include:
10 N-(Bis (2-hydroxy-4-niiro phenyl) N'-(dianisdine) diurea
4-Methylene bis(N-(2-chloro phenyl) N'-(2-hydroxy 4-nitro phenyl) urea)
Exemplified compounds of Formula (I) include:
N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenylurca:
15 N-|5-Nitro-2-hydroxyphenyl]-N'-phenyl urea
3-Hydroxy-4-{ [(phenylamino)carbonyl]amino}benzamide
N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea
2-{ [(Phenylamino)carbonyljamino >thi phenol
N-(2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea
20 N-[2-Hydroxy-4-(trifluoromethyl)phcnyI]-N'-phenyl urea
N-(2-Hydroxy-4-nilrophenyl)-N'-(2-hydroxy-4-nitropheny]) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-thiourea
N-(4-Niiro-2-(phenylsulfonylamino)phenyl)-N'-phcnyl urea
N-(2-Hydroxy-5-nitrophenyl)-N'-(3-meihoxy-2-thienyl)urea
25 N-(2-Hydroxy-4-nilrophenyl)-N'-(3-methoxy-2-thienyl)urea
N-(2-Hydroxy-4-nilrophenyl)-N'-(3-mcthoxyphcnyl)urea
N-( 2- Hvdroxy-4-nitrophenyl)-N'-(2-methoxy phenyl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-trinuoromelhylphcnyl)urca
N T -(2-Hydroxy-4-nitrophenyl)-N'-(2-trinuoromethylphcny] )urca
30 N-(2-Hvdriixy-4-nitrophenyl)-N'-(4-trinuoromcthylphcnyl turca
N-(2-Hydroxy-4-niirophenyl)-N'-(2-bromophenyl)urca
N-(2-Hvdroxy-4-nitrophenyl)-N'-(3-bromophcnyl)urca
N-(2-H\di"oxy-4-niirophenyl)-N'-(4-bromophcnyl)urea
N-( 2- Hydn)xy-4-niirophcnyl)-N'-(2-phcnyl phenyl )urca
35 N-(2-Hydroxy-4-nitrophenyl)-N'-( 1 -naphthyl)urca:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitrophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nuorophenyl)urea
N-(2-Hvdroxy-4-nurophenyl)-N'-(2.6-dinuorophenyl )urca
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N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea
N-(2-Hydroxy-4-niirophenyl)-N'-(2-ethylphenyl)urea
N-{2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethoxyphenyl)urca
N-(2-Hydroxy-4-nitrophenyl) N'-(2-methylthiophenyl) urea
5 N-(2-Hydroxy-4-niirophenyl) N'-(2-chloro 6-meihyl phenyl) urea
N-(2-Hydroxy-4-nilrophenyl) N'-(2-sulfoxymethyl phenyl) urea
N-(4-Trifluoromethyl-2-hydroxy phenyl) N'-(2-bromo phenyl) urea
N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-bromophenyl) urea
N-(4-Trinuoromethyl-2-hydroxy phenyl) N'-(2-phenyl phenyl) urea
10 N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-phenyl phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2,3-dichloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N"-(2.4-dichloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2-chloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-C2.4-dibromo phenyl) urea
15 N-(2-Hydroxy-l-napthyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N , -(2-methyl phenyl) urea
N-[4-(Benzylamino)carbonyl-2-hydroxyphenyl]-N'-(2-bromophenyl)urea
20 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenoxy phenyl) urea
N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy 3-napthyl) N'-(2-bromo phenyl) urea;
N-(3.4-Difluoro 2-hydroxy phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea
25 N-f2-Hydroxy 4-methyl phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-nitro phenyl) N'-(2-phenylamino phenyl) urea
N-(2-Hydroxy 3-carboxyphenyl) N'-(2-bromo phenyl) urea
N-(2-Sull~hydryl 4-bromo phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea
30 N-(2-Hydroxy 4-nitro phenyl) N , -(2-bromo phenyl) thiourea
N-|(2-Phenylsullamido) 4-cvanophenyl]- N'-f2-bromo phenyl) urea
N-(2-{ Amino sulfonamide phenyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sullonyl siyryl) phenyl) N'-(2-bromo phenyl) urea
2-[(3.4 Di-methoxyphenylsuli"onyl)amino] phenyl) N'-(2-bromo phenyl) urea
35 N-(2-|(4-AcciamidophenylsuironyDamino] phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonyl (2-lhiophenc) phenyl) N'-(2-bromo phenyl) urea
N-(2-( Amino sullonyl (3-tolyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-( Amino sullonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea
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N-(2-(Amino sulfonyl benzyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphcnyl)urea
N-[2-Hydroxy-5-cyanophenyl]-N'-[2-bromophenyl) urea
N-[2-Hydroxy-3-nuorophenyl]-N'-[2-bromophcnyl| urea
5 N-[2-Hydroxy-3-nuoro-5-bromophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-chlorophenyl]-N'-[2-bromophenyl) urea
N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3.4-diphenyl-phenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophcnyl| urea
10 N-|2-hHydroxy-3-glycincarbonylphenyl]-N'-f2-bromophenylJ urea
N-[2-Hydroxy-3,5-dichlorophenyl]-N"-[2-bromophenyl] urea
N-[2-Hydroxy-3-nitrophenyl]-N"-[2-bromophenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-f2-brornophenyl] urea
15 N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-phenylpheny]] urea
N-|2-Hydroxy-4-cyanophenyl]-N'-[2-meihylphenyl) urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyll urea
20 N-[2-Hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromcthylphenyI] urea
N-[2-Hydroxy-3-n-propylphenyl]-N'-[2-bromophcnyl) urea
N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromophcnyl 1 urea
N-[2-Hydroxy-3-phcnylaminocarbonyl phenyl|-N , -|2-brc)mophcnyl | urea
25 N-[2-Hydroxy-3-cyano-4-methylphenyl]-N'-f2-bromopricnyl| urea
N-l2-Hydroxy-4-carbophcnyl phenyl]-N'-[2-bn>mophcnyI | urea
N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromnphcny] | urea
N-[3-Benzyloxy-2-hydroxyphenyl]-N'-[2-bromophcnyl| urea
(E)-N-|4-[2-CMethoxycarbonyl) cihenylJ-2-hydroxyphcnyl|-N'-|2-bromophenvl| urea
30 (E)-N-[3-[2-(Melhoxycarbonyl) clhenyl]-2-hydrnxyphcnyl|-N , -f2-bnimophenvl | urea-\"-|2-
bromophenyll urea
(E)-N-[3-[2-(Aminocarbonyl) cihenyl]-2-hydroxyphcnyl|-N'-|2-hromophcnvl |urea-\"-| 2-
broniophcnyl] urea
(E)-N-[4-|2-(Aminocarbonyl) eihenyl]-2-hydroxyphcnyl|-N'-|2-bronn)phenyl|urca-N'-|2-
35 bromophenyl] urea
N-[2-Hydroxy-4-benzamidc phenyl]-N'-[2-bromophenyl] urea
N-[4-Aminocarbonyl-2-hydroxyphenyl]-N'-f2-bromophenyl] urea
N-(2-Hydroxy-3.5.6-tnniiorophenyl)-N'-(2-bromophcnyl)urea
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N-(2-Hydroxy-3-nuoro-4-trinuoromethylphcny])-N'-(2-bromophcnyl)urea
N-f2-Hydroxy-3-iodophcnyl)-N'-(2-bromophcnyl)urca
N-[2-[f[2-(Trinuoromcthyl)phcnyl)sulf'onyl]amino|phenyl]-N'-(2-br()mophcnyl)urea
N-(2-Bromopheny])-N'-f2-dimethylaminosuHonylamino]phenyl|urca
5 N-f2-(Phenethylsullonylamino)phenyl]-N'-(2-bromophenyl)urca
N-[2-f(2-Acetamido-4-melhylthiazol-5-yl)sul!"ony]aminojpheny]|-N"-(2-br(>mophenyl)urca
N-[2-Hydroxy-4-cyanophenyll-N'-[4-phcnylphcnyI| urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl ] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea
10 N-[2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl| urea
N-[2-Hydroxy-5-fluorophenylJ-N'-[2-bromophenyl] urea
N-[2-Hydroxy-5-trifluoromethylphenyl)-N'-[2-bromophenyl) urea
N-[2-Hydroxyphenyl]-N'-f2-bromophenyl) urea
N-rTrans-3-styrl-2-hydroxyphenyl]-N'-f2-bromophenyl| urea
15 N-[2-Hydroxy-3.4-dichlorophenyl]-N'-I2-methoxyphenyl| urea
N-f2-Hydroxy-3.4-dichlorophenyl]-N'-[4-methoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[3-trinuoromethylphenyl| urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N , -[2-phcnylphcnyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[4-phcnylphcnyl] urea
20 N-[2-Hydroxy-3.4-dich]orophenyl]-N*-f2.3-dichlorophenyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-f3-trinuoromethylphenyl] urea
N-i2-Hydroxy-3-naphthyl]-N'-[2,3-dichlorophcnyl| urea
N-[2-[(2.3-Dichlorolhicn-5-yl)]sulfonylarnino]phcnyll-N'-(2-brom()phcnyl)urca
N-[2-[(3.5-Bisirinuoromethylphenyl)suironylarninolphcnyl|-N'-(2-bn)mophcnyl)urca
25 N-[2-[(2-BenzylVsullonylamino]-(5-trinuororncthyl)phcnyl]-N'-f2-br(>nu>plicnvl)urca
N-[2-|2-(3-Niirophcnyl)sulfonylaminolphcnyl|-N , -(2-bromophcnyI)urca
N-[2-[2-(4-Phenoxyphcnyl)sull'onylarnino|phenyl|-N'-(2-bromophenvl) urea
N-[[2-(lS)-IO-Camphorsulfonylamino)phenyl|-N'-(2-bromophcnyl)iirca
30 N-[[2-( 1R)- l()-Camphorsulfonylamino]phcnyll-N'-(2-bromophenyl)urca
N-[2-[2-(2-Niiro-(4-tritluoromethyl)phcnyl)sullbnylaminojphcnyl-N , -(2-bn)m()phenyl)urea
N-(2-Hydroxy-4-azidophenyl)-N'-(2-iodophcnyl)urca
N-(2-Hydroxy-3-azidophcnyl)-N , -(2-bromophenyl)urca
N-[2-Hydroxy-3-cyanophcnyl]-N'-[2-mcih()xyphcnyl] urea
35 N-[2-Hydroxy-3-cyanophcnylJ-N'-[3-tririuoromcihylphenyl] urea
N-[2-Hydroxy-3-cyanophenyl)-N'-[2-phcnylphcnyll urea
N-f2-Hydroxy-3-cyanophenyl]-N'-[2,3-dichlorophenyl) urea
N-[2-Hydroxy-4-isopropylphenyl]-N*-[2.3-dichlorophenyl) urea
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N-[2-Hydroxy-4-isopropylphenyl]-N -|2-chloro-5-trinuoromcthylphcnyl) urea
N-|2-Hydroxy-3-phcny]phenyl|-N -[2.3-diehiorophenyl] urea
N-f2-Hydroxy-5-niirophcnyl]-N'-[2-mcihoxyphcnyl] urea
N-|2-Hydroxy-5-nitrophcnyll-N'-[3-lrinuoromcthylphenyl| urea
5 N-[2-Hydroxy-5-nilrophenyl|-N'-[2-phenylphcnyll urea
N-[2-Hydroxy-5-niirophenyl|-N'-f2,3-dichlorophenyl] urea
N-|2-Hydroxy-5-cthyl.sultonylpheny]|-N'-[2.3-dichlorophenyl| urea
N-f2-(2-Amino-(4-trifluoromethyl) phenyl) sullonylamino] phenyl]- N -(2-
bromophenyDurea
10 N-[2-(Aminosullonyl phenyl) 3-amino phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy-3,4-dichlorophenyl]-N'-[2,4 dimeihoxyphenyl] urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-|2-chloro-5-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-naphthyIl-N'-[3-lrifluoromethylphenyl] urea
N-[2-Hydroxy-5-naphthalenesulfonic acid]-N'-f2-bromophenyll urea:
15 N-[2-Hydroxy-4-naphlhalenesullonic acid]-N'-|2-bromophenyl] urea:
1 . 1 '-(4-Methyl-2-phenylene)bis[2-thio-3-3-iolylurea]
N-(2-Carboxyphenyl)-N-phenylurea
N-(2-Hydroxy-4-nilrophenyl)-N'-phenylurca:
1- (2-Carboxyphenyl)-3-(4-chlorophcnyl)urca ;
20 2-(3,4-Dichloropheny]carbonyldiimino)-5-trinuoromethylbenzt)ic acid:
2- (4-Chlorophenylcarbonyldiimino)-. < >-U'inuor()mcihylbenzoic acid:
l-(p-Anisyn-3-(2-carboxyphcnyl)urca;
l-(2-Carboxyphcnyl)-3-(3-nuorophcnyl)urca:
l-(2-Carboxyphcnyl)-3-(3-chlorophcnyl)urca:
25 1 -(m-Anisyl)-3-(2-carboxyphneyl)urea:
1 -(o-Anisyl)-3-(2-carboxyphcnyl)urca :
1 -(2-Carboxyphenyl)-3-(3.4-dichlorophcnyl )urca:
i -(2-Carboxyphcnyl)-3-(2.4-dichlorophciiyl )urca;
\'-(5-Ch^oro-2-hyd^oxy-4-nllrophcnyl)-N , -phenyl urea:
30 N-(2-Hydroxv-4-nitrophcnyl)-N'-(4-nitrophcnyl)urca;
Prclcrcd compounds of Formula (I) include:
N-(2-Hydroxy-4-niln)phenvl)-N'-(2-meihoxyphenyl)urea
N-(2-Hydrox\ -4-nilrophcnyl )-N'-( 2-bromophenyl )urea
35 N'-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphcnyl)urea
N-(2-Hydroxy-4-niLrophenyl)-N'-(2-mcthylthiophenyl)urca
N-(2-Hydrox\ -4-niirophenyl )-N'-(2.3-dichlorophenyl)urea
N-l2-hydroxy 4-nitro phenyl) N'-(2-chloro pnenyl) urea
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N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-mclhylcnedioxyphcnyl)urea
N-(2-Hydroxy-4-niirophcnyl)-N'-(2-mcihoxy-3-chiorophenyl)urea
N-(2-hydroxy 4-nitro phenyl) N'-(2-phcnyloxy phenyl) urea
N-(3-Chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea
5 N-(2-Hydroxy-3-glycinemethylestercarbonylphenyl)-N , -(2-bromophcnyl)urea
N-(3-Nitro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3,4-diehlorophenyl)-N'-(2-bromophenyl)urea
N-(3-Cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
I ( ) N-f 2-Hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea
N-Q-Hydorxy-4-cyanophenyl-N'-(2.3-dichlorophenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methylphenyl)urea
N-(2-Hydroxy-3-cyano-4-methylphenyl)-N , -(2-bromophenyl)urea
15 N-(4-Cyano-2-hydroxyphenyl)-N'-(2-lrinuoromethylphenyl)urea
N-(3-Trinuoromethyl-2-hydroxyphenyl)-N , -(2-bromophenyl)urea
N-(3-Phenylaminocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(2-hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea
N-(2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea
20 N-(2-phenylsul!'onamido)-4-cyanophenyl-N'(2-bromo phenyDurea
(E)-N-[3-K2-Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N , -(2-bromophenyl)urea
N-(2-Hvdroxy.3.4-dichlorophenyl)-N'-(2-methoxyphenyl)urca
N-f2-Hydroxy.3.4-dichlorophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-3.4-dichlorophenyl)-N'-(2.3-dichlorophcnyl)urca
25 N-f2-Hydn)xy-5-niirophenyl)-N'-(2.3-dichl()rophenyl)urca
N-(2-Hvdrox\ - 3-cyanophenyl)-N"-(2.3 dichlorophenyburea
As used herein, "optionally substituted" unless specifically defined shall mean such
groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted
30 Ci-ioalkyl: C|-I0 alkoxy. such as mcthoxy or cthoxy: S(0) m ' C\. |() alkyl. wherein m' is 0.
1 or 2. such as methyl thio. methyl sulfinyl or methyl sulfonyl: amino, mono & di-subsmuicd
amino, such as in the NR4R5 group: NHC(0)R4: C(0)NR4R5; C(0)OH: S(0)2NR4R5:
NHS(0)2R|3. Ci-io alkyl. such as methyl, ethyl, propyl, isopropyl. or l-butyl;
halosubsiuutcd C| .]() alkyl. such CF3: an optionally substituted aryl. such as phenyl, or an
35 optionally substituted arylalkyl. such as benzyl or phenethyl. optionally substituted hctcrocylic.
optionally substituted heterocylicalkyl. optionally substituted heteroaryl. optionally substituted
heicroaryl alkyl. wherein these aryl . hctroaryl. or heterocyclic moieties mav be substituted one
to two times by halogen: hydroxy: hydroxy substituted alkyl: C 1 -]() alkoxy: S(O)m'Ci-K)
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alkyl; amino, mono & di-substituted amino, such as in the NR4R5 group: Ci-io alkyl. or
halosubstituied C| - 10 alkyl, such as CF3.
Rl3 is suitably C|-4 alkyl, aryl. aryl Ci-4alkyl, heteroaryl. hcteroary]C]-4alkyI,
heterocyclic, or heterocyclicC|-4alkyl.
5
Another aspect of the present invention are the novel compounds of Formula (II), or a
pharmaceutically acceptable salt thereof, as described below, which are also useful in inhibiting
the binding of IL-8 to its receptors in a mammal in need thereof. This invention also relates to
the pharmaceutical compositions comprising a compound of Formula (II) and a
1 0 pharmaceutically acceptable diluent or carrier Compounds of Formula (II) are also useful lor
treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a
or P receptor and which method comprises administering an effective amount of a compound
of Formula (II) or a pharmaceutical^ acceptable salt thereof. Compounds of Formula
(II) are represented by the structure:
wherein
X is oxygen or sulfur:
R is any functional moiety having an lonizable hydrogen and a pKa of 10 or less:
Rl is independently selected from hydrogen: halogen: nilro: cyano: halosubstituied C 1. 10
20 alkyl: C 1-10 alkyl: C2- 10 alkenyl: Ci-io alkoxy: halosubstituied Ci - 10 alkoxy: a/.ide:
S(0)tR4: hydroxy; hydroxyCi-4alkyl: aryl; aryl C|-4 alkyl; aryloxy: arylCi.4 alkyloxy:
heteroaryl: heteroarylalkyl: heterocyclic. heterocyclicC 1 -4alkyl: hcicroarylC 1.4 alkyloxv:
aryl C2-K) alkenyl; heteroaryl C2- 10 alkenyl: heterocyclicC2-l() alkenyl: NR4R5: C2- 10
alkenyl C(0)NR4Rs; C(0)NR4R5: C(0)NR4Rl(): S(C»3H: S(0)3R«: C|.|() alkyl
25 C(0)R 1 1 : C2- 1 0 alkenyl C(0)R 1 1 : C2- 1() alkenyl C(0)OR 1 1 : C(0)R 1 1 ; C(0)OR 12:
OC(O) Ri 1: NR4C(0)Ri \ : or iwo Ri moieties together may form 0-(CH2)sO- or a 5 to f>
membered unsaturated ring:
1 is 0. or an integer having a value of I or 2:
s is an integer having a value of 1 to 3:
30 R4 and R5 arc independently hydrogen, optionally substituted C1.4 alkyl. optionally
substituted ary l. optionally substituted aryl C]-4alkyl. optionally substituted heteroaryl.
optionally substituted heteroaryl Ci-4alkyl, heterocyclic. heterocyclicC 1 .4 alkyl. or R4 and
R5 together with die nitrogen to which they are attached form a 5 to 7 member ring which
may optionally comprise an additional heieroaiom selected from O/N/S:
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Y is independently selected from hydrogen: halogen; nitro; cyano: halosubsiiiuicd Ci - 10 alkyl:
C i . | o alkyl: C2- 10 alkenyl: C i _ io alkoxy: halosubstituted C | . k> alkoxy: azidc: S(0) t R4:
hydroxy: hydroxy C ] -4alkyl ; aryl; aryl Ci-4 alkyl: aryloxy; aryl Cj-4 alkyloxy: heteroaryl:
hetcroarylalkyl: heteroarylC | .4 alkyloxy: heterocyclic, heterocyclic C[-4aJkyl: aryl C2-K)
5 alkenyl: heteroaryl C2- 10 alkenyl: heterocyclic C2- 1 0 alkenyl: NR4R5: C2- 1 0 alkenyl
C(0)NR4R5". C(0)NR4R5; C(O)NR4Rl0: S(0)3H: S(0)3R 8 : C | - 1 () alkyl C(0)R 1 1 :
C2- 1 () alkenyl C(0)R 1 1 : C2- 1 0 alkenyl C(0)OR 1 1 ; C(0)R 1 1 : C(0)OR 12: OC(O) R 1 | :
NR4C(0)Ri 1 : or two Y moieties together may form 0-(CH2) s O- or a 5 to 6 mcmbered
unsaturated ring;
10 n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3:
R8 is hydrogen or C 1 .4 alkyl;
RlO is C 1-10 alkyl C(0)2R8:
Rl 1 is hydrogen. C1-4 alkyl, optionally substituted aryl. optionally substituted aryl C|-4alkyl.
15 optionally substituted heteroaryl, optionally substituted heteroarylC |-4alkyl. optionally
substituted heterocyclic, or optionally substituted heterocyclic | -4alkyl:
Rl2 is hydrogen, C]-io alkyl, optionally substituted aryl or optionally substituted arylalkyl:
E is optionally selected from
asienx * denoting point of attachment of the ring, with at least one E being present;
or a pharmaceuiically acceptably salt thereof.
Suitably, the variables for Formula (II). such as X. R. Rj. R4 . R5. R 6 R7. R*. Ri,
Y. R a . Rb. Rc- n. m. and s terms, etc. arc as defined in Formula (I) above The E rim:
denoted by its point of attachment through the astcnx (*) may optionally be present. I! il 11 i.s
not present the ring is a phenyl moiety which is substituted by the R and R 1 terms as shown
At least one E ring is necessary. The E ring may be .substituted by the R | moiety 111 any rim:,
saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated
ring(s).
Exemplified compounds of Formula (III) arc
N-[2-hydrox> -5-indanone]-N'-(2-bromophenyl | urea.
N-| l-hydroxynuorcne]-N'-[2-bromophcnyl) urea;
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N-f3-hydroxy-9,l()-anthraquinon-2-yl|-N'-[2-bromophenyl| urea
Another aspect of the present invention are the novel compounds of Formula (III), or a
pharmaceutical^ acceptable salt thereof, as described below, which are also useful in inhibiting
the binding of IL-8 lo its receptors in a mammal in need thereof. This invention also relates to
the pharmaceutical compositions comprising a compound of Formula (III) and a
pharmaceutically acceptable diluent or carrier. Compounds of Formula (III > arc also useful for
treating a chemokine mediated disease, wherein the chemokinc is one which binds to an IL-X a
or P receptor and which method comprises administering an effective amount of a compound
of Formula (III) or a pharmaceutically acceptable salt thereof Compounds of Formula (III ) are
represented by the formula:
wherein
X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less:
Rl is independently selected from hydrogen: halogen: nitro: cyano: halosubsututcd Ci-io
alkyl: C|.]() alkyl; C2- 10 alkenyl: C\-\Q alkoxy. haJosubstiiutcd C ] - 1<) alkoxy: a/.idc:
S(0) t R4; hydroxy; hydroxyC ] -4alkyl; aryl: aryl Ci-4 alkyl; aryioxy: arylCi-4 alkyloxy:
hcteroaryl: heteroarylalkyl: heterocyclic, heterocyclic |-4alkvl: hcieroarylC | .4 alkyloxv:
aryl C2-10 alkenyl; hetcroaryl C2- 10 alkenyl: hctcrocyclicC2- 10 alkenyl: NR4R v C2-K)
alkenyl C(0)NR4R5; C(0)NR4R5; C(0)NR4Rl(): S(0)?H: S(0)3Rs: C |- in alkyl
C(0)R 1 1: C2-10 alkenyl C(0)R 1 1 : Q- 10 alkenyl C(0)OR 1 | : C(0)R | 1 : C(0)OR 1 2:
OC(O) Ri 1 : NR4C(0)R 1 1 : or two R 1 moieties together may form 0-(CH2) s O- or a 5 10 6
membered unsaturated ring:
t is 0. or an integer having a value of 1 or 2:
s is an integer having a value of 1 to 3:
R4 and Rs are independently hydrogen, optionally substituted Ci-4 alkyl. optionally
substituted aryl, optionally substituted aryl C|-4alkvl. optionally substituted hcteroaryl.
optionally substituted heteroaryl Cj-4alkyl. heterocyclic, heterocyclic |-4 alkyl. or R4 and
R5 together with the nitrogen 10 which they are attached form a 5 to 7 member ring which
may optionally comprise an additional hetcroalom selected from O/N/S:
Y is independently selected from hydrogen: halogen; nitro: cyano: halosubsututcd C 1 . 10 alkyl:
Ci-io alkyl: C2-10 alkenyl: Ci-i(» alkoxy: halosubstituted Cj .]() alkoxy; a/.idc: S(0) t R4:
(Y)n
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- 17 -
hydroxy; hydroxyC|-4alkyl: aryl; ary] Ci- 4 alkyl: aryloxy: arylCi-4 alkyloxy: heieroaryl:
heleroarylalkyl; heieroarylC ] .4 alkyloxy; hcicrocyclic, heterocyclic i_4alkyl: aryl C2-10
alkenyl; heieroaryl C2- 10 aJkcnyl; heterocyclic^- 1() alkenyl; NR4R5: C2-K) alkenyl
C(0)NR4R5: C(0)NR4R5: C(0)NR4Rio: S(0) 3 H; S(0) 3 R8: C M0 alkyl C(0)Ri ];
C2- 1 0 alkenyl C(0)R 1 1: C2-IO alkenyl C(0)OR 1 1 ; C(0)R 1 1 : C(0)OR 1 2; OC(O) R\\:
NR 4 C(0)Ri 1 : or two Y moieties together may form 0-(CH2) s O- or a 5 to 6 mcmbered
unsaturated ring;
n is an integer having a value of 1 to 3:
m is an integer having a value oi" I to 3;
R8 is hydrogen or C | .4 alkyl;
R 10 is C i-io alkyl C(0)2R8;
Rj 1 is hydrogen, C]- 4 alkyl, optionally substituted aryl, optionally subsutuied aryl Ci_4alkyl.
optionally substituted heieroaryl, optionally subsutuied heieroarylC i_4alkyl. optionally
substituted heterocyclic, or optionally substituted heterocyclic ] -4alkyl;
Rl2 is hydrogen. C]. 10 alkyl, optionally substituted aryl or optionally substituted arylalkyl:
or a pharmaceutical^ acceptably salt thereof.
Suitably, the variables, etc. for Formula (II) are the same as those defined for Formula
(I) above, such as for example the R variable
Exemplified compounds of Formula (III) are N-(2-Hydroxy-4-nitrophenyl)-N'-(3-
meihoxy-2-thienyl)urca ; and N-(2-hydroxy-5-nitrophcnyl)-N'-(3-methoxy-2-thicny])urca.
Another aspect of the present invention is the novel compounds of Formula (la), a
subset of compounds of Formula (I) useful for treating a chemokine mediated disease as
defined herein. This invenuon also relates to the pharmaceutical compositions comprising a
compound of Formula (la) and a pharmaecuiically acceptable diluent or carrier. The
compounds of Formula (la) are represented by ihe strucuiurc:
wherein
X is oxygen or sulfur;
R a is an alkyl. aryl. arylC j - 4 alkyl. heieroaryl. heieroaryl C i- 4 alkyl. heterocyclic, or a
heterocyclic C 1 -4alkyl moiety, all of which may be optionally substituted;
NHS(0) 2 R b
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Rb is a NR6R7, alkyl. aryl. arylC ] -4alkyl. aryl C2-4alkenyl, heieroaryl. heieroarylC ] -4alkyl.
hetcroarylC2-4 alkenyl. heterocyclic, or heterocyclic Ci-4alkyl. or a heterocyclic
C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times
independently by halogen; nitro: halosubstituted C1-4 alkyl; C1-4 alkyl: Ci-4 alkoxy:
5 NRoC(0)R a : C(0)NR6R7- S(0)3H. or C(0)OC | .4 alkyl;
R6 and R7 arc independently hydrogen or a C | .4 alkyl group, or R<s and R7 together with the
nitrogen to which they arc attached form a 5 to 7 member ring which ring may optionally
contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or
sulfur, which ring may be optionally substitued;
10 R9 is hydrogen or a C | .4 alkyl. preferably hydrogen;
Rl is independently selected from hydrogen: halogen: nitro; cyano: halosubstituted C\. 10
alkyl: C l-io alkyl: C2-K) alkenyl; Ci- 10 alkoxy: halosubstituted Cj. 10 alkoxy; azide:
S(0) t R4; hydroxy: hydroxy C1.4alk.yl: aryl; aryl C 1-4 alkyl; aryloxy: aryl Cj-4 alkyloxy:
heteroaryl: heteroarylalkyl: heterocyclic, heterocyclic Ci-4alkyl: heieroaryl Cj_4 alkyloxy:
15 aryl C2-10 alkenyl: heieroaryl C2- 10 alkenyl: heterocyclicC2- 10 alkenyl: NR4R5; C2-10
alkenyl C(0)NR4R5: C(0)NR4R<>; C(0)NR4Ri(); S(0)3H; S(0)3R8: Ci- 10 alkyl
C(0)R 1 1 ; C2- 1 0 alkenyl C(0)R 1 1 : C2- 10 alkenyl C(0)OR 1 1 : C(0)R 1 1 ; C(0)OR 12:
OC(O) Rl 1 : NR4C(0)R [ 1 ; or two R | moieties together may form 0-(CH2)sO- or a 5 to 6
membered unsaturated ring;
20 1 is 0. or an integer having a value of 1 or 2:
s is an integer having a value of 1 to 3:
R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl. optionally
substituted aryl. optionally substituted aryl C 1 -4alkyl, optionally substituted heieroaryl.
optionally substituted heieroaryl C|-4alkyl. heterocyclic. hetcrocyclicC 1.4 alkyl. or R4 and
25 R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which
may optionally comprise an additional heteroatom selected from O/N/S:
Y is independently selected from hydrogen: halogen: nitro: cyano: halosubstituted Ci - 10 alkyl:
C1-10 alkyl: C2- 10 alkenyl: Ci - 10 alkoxy: halosubstituted Cmo alkoxy: azide: S(0)[R4:
hydroxy: hydroxyC |-4alkyl: aryl; aryl Ci-4 alkyl: aryloxy: arylCi.4 alkyloxy: heieroaryl:
30 heteroarylalkyl: heieroarylC 1 .4 alkyloxy: heterocyclic. hetcrocyclicC ] -4alkyl: aryl C2- 10
alkenyl: heieroaryl C2-10 alkenyl: hetcrocyclicC?- 10 alkenyl: NR4R5: C2-10 alkenyl
C(0)NR4Rs: C(0)NR4R.5: C(0)NR 4 R in: S(OnH: S(0)3R«: C 1 .|() alkyl C(0)R 1 1 :
C2- 10 alkenyl C(0)R| 1 : C2- 1 0 alkenyl C(0)ORi i:CfO)R| \ : C(0)OR|2: OC(O) Rl |:
NR4C(0)R] 1 : or two Y moieties together may form 0-(CH2) s O- or a 5 to 6 membered
35 unsaturated ring:
n is an integer having a value of 1 to 3:
m is an integer having a value of 1 to 3:
R8 is hydrogen or C]-4 alkyl:
WO 96/25157
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19
R|0 is C ]- 10 alky] C(0)2R8;
R| 1 is hydrogen, C |-4 alkyl, optionally substituted aryl, optionally substituted aryl C|-4alkyl.
optionally substituted heteroaryl, optionally subsututed heteroarylC i _4alkyl, optionally
substituted heterocyclic, or optionally substituted heterocyciicCi-4alkyl;
Rl2 is hydrogen, C i - u> alkyl, optionally substituted aryl or optionally substituted arylalkyl;
or a pharmaceutically acceptably salt thereof.
A preferred ring substitution for R\ variable is monosubsUtuted in the 3-position. or the
4- position, or di-substituted in the 3.4- position. The substituent group is suitably an electron
withdrawing moiety. Preferably Rj is nitro. halogen, cyano, tritluoromethyl group, or
C(0)NR4R.5
While Y may be substituted in any of the 5 ring positions, preferably the ring with the
Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being
unsubstitutcd. If the ring is di-substituted. substituents are preferably in the 2'-, 3 - positions
of a monocyclic ring. While both R] and Y can both be hydrogen, it is prefered that at least
one of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd
m are each equal to 1 or more.
Y is more preferably a mono -subsututed halogen, disubstituted halogen, mono-
substituted alkoxy. disubstituted alkoxy, methylenedioxy. aryl, or alkyl. preferably these
groups are substituted in the 2'- position or 2'-,3'-position.
Exemplified compounds of Formula (la) are
N-(4-Nuro 2-(phcnylsulfonylamino)phcnyl)-N'-phcnyl urea
N-[(2-Phcnylsulfamido)4-cyanophenyl]- N'-(2-bromo phenyl) urea
N-(2-(Amino suifonamido phenyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-(Ammo sulfonyl styryl) phenyl) N'-(2-bromo phenyl) urea
2-[(3.4 Di-mcihoxyphenylsulfonyl)amino) phenyl) N'-(2-bromo phenyl) urea
N-(2-[(4-Aceiamidophenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonyl (2-thiophene) phenyl) N'-(2-bromo phenyl) urea
N-(2-( Amino sulfonyl (3-tolyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-( Amino sulfonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea
N-(2-( Amino sulfonyl benzyl) phenyl) N'-(2-bromo phenyl) urea
N-|2-[||2-(Trinuoromcthyl)phenyl)sulfonyl]amino]phenyl|-N'-(2-bromophenyl)urea
N-(2-Bn)moplicnyl)-N'-f2-dimethylaminosullonylamino]phcnyl]urca
N-[2-(Pheneihylsul!onylamino)phenyl]-N'-(2-bromophenyl)urea
N-[2-f(2-AcLUamid()-4-mcthylthiazol-5-yl)sulfonylaminoJphenyl]-N'-(2-bromophenyl)urea
N-[2-|(2.3-Dichlorothien-5-yl)]sulfonylamino]phenyl)-N'-(2-bromophenyl)urea
N-[2-[(3.5-Bistnnuoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urca
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- 20 -
N-[2-[(2-Benzyl)sullony]arnino]-(5-trinuoromeihyl)phenyl|-N'-(2-bn)mophcnyl)urea
N-| 2-| 2-(3-Nitrophenyl)sullonylamino Iphcnyl l-N'-(2-bromophenyl )urea
N-[2-[2-(4-Phenoxyphenyl)sult"onylamino]phenyl|-N'-(2-bromophcnyl) urea
5 N-[[2-( I S)- l()-Camphorsulfonylamino]phenyl]-N'-(2-bromophcnyl)urea
N-[[2-(lR)-10-Camphorsuli"onylamino]phenyl]-N'-(2-bromophcnyl)urca
N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sult'onylamino]pheny]-N'-(2-bromophenyl)urcii
N-(2-(2-Amino-(4-trifluoromethyl) phenyl) sult'onylamino] phenyl]- N'-(2-
bromophenyOurea
10 N-[2-(aminosulfonyI phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea
Another aspect of the present invention is the novel compounds of Formula (lb), a
subset of compounds of Formula (I) useful for treating a chemokine mediated disease. This
invention also relates to the pharmaceutical compositions comprising a compound of Formula
15 (lb) and a pharmaceutical^ acceptable diluent or carrier. The compounds of Formula (lb) arc
represented by the strucuture:
wherein
20 X is oxygen or sulfur;
X i is oxygen or sulfur;
R i is independently selected from hydrogen; halogen; niiro; cyano: halosubsiuuted C | - 1<>
alkyl; C\-\o alkyl: C2-10 alkenyl; C i_ i () alkoxy: halosubsiiiuied C\.\{) alkoxy; a/ide;
S(0)tR4; hydroxy; hydroxyC i-4alkyl; aryl; aryl Ci-4 alkyl: ar>'loxy: arylC|-4 alkyloxy;
25 hetcroaryl; heteroarylalkyl : heterocyclic, heterocyclic C i -4alkyl; hctcroaryl C | -4 alkyloxy :
aryl C2-10 alkenyl; hetcroaryl C2-K) alkenyl; heierocyciicC2-l() alkenyl: NR4R5: C2-10
alkenyl C(0)NR4Rs; C(0)NR4R5: C(0)NR4Rl(): S(0)3H; S(0)3Rr: C 1 - 10 alkyl
C(0)R 1 ] : C2- 10 alkenyl C(0)R 1 1 : C2- 10 alkenyl C(0)OR ] 1 ; C(0)R 1 1 : C(0)OR 12:
OC(O) R 1 1 ; NR4C(0)R ] 1 : or two R 1 moieties together may form 0-(CH2)sO- or a 5 to b
3() membcrcd unsaturated ring;
t is 0. or an integer having a value of 1 or 2:
s is an integer having a value of 1 to 3:
R2 is a substituted aryl. heteroaryl, or heterocyclic ring which ring has a functional moiety
providing the lonizable hydrogen having a pKa of 10 or less:
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- 21 -
R4 and R<s arc independently hydrogen, optionally substituted C1.4 alkyl, optionally
substituted aryl, optionally substituted aryl C |_ 4 alkyl, optionally substituted heteroaryl.
optionally substituted heteroaryl C 1 -4alkyl, heterocyclic. heterocyclic 1.4 alkyl. or R 4 and
R5 together with the nitrogen to which they are attached form a 5 to 7 member nng which
may optionally comprise an additional heteroatom selected from O/N/S:
Y is independently selected from hydrogen: halogen: nilro; cyano: halosubsiituted C 1 - 10 alkyl:
C 1- 10 alkyl: C2-10 alkenyl: C | . |() alkoxy: halosubsiituted C 1 . 10 alkoxy: azidc: S(0)[R 4 :
hydroxy: hydroxyCi- 4 alkyl: aryl; aryl C|. 4 alkyl: aryloxy: arylCi.4 alkyloxy: heicroaryl:
heteroarylalkyl: heteroarylC \ .4 alkyloxy; heterocyclic. heterocyclicC]-4alkyl: aryl C2-I0
alkenyl: heteroaryl C2- 10 alkenyl: heterocyclicC2- 10 alkenyl: NR4R5: C 2 - 10 alkenyl
C(0)NR 4 R 5 : C(0)NR4R 5 : C(O)NR4Rl 0 ; S(0) 3 H; S(0)3Rg: Cj-K, alky] C(0)Ri 1 :
C2- 1 0 alkenyl C(0)R 1 1: C2-10 alkenyl C(0)OR 1 1 : C(0)R 1 1 : C(0)OR 1 2 : OC(O) R\\:
NR4C(0)R 1 1 ; or two Y moieties together may form 0-(CH2) s O- or a 5 to 6 membered
unsaturated ring:
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;
Rg is hydrogen or C 1 .4 alkyl;
R 10 is C i - 10 alkyl C(0)2Rg:
Rl 1 is hydrogen, C 1.4 alkyl. optionally substituted aryl. optionally substituted aryl Ci- 4 alkyl,
optionally substituted heicroaryl, optionally substituted heteroarylC |-4alkyl, optionally
substituted heterocyclic, or optionally substituted heterocyclic |- 4 alkyl:
R 1 2 is hydrogen. C ] . 10 alkyl. optionally substituted aryl or optionally substituted arylalkyl:
or a pharmaceutical^' acceptable salt thereof.
Suitably, the variable, etc. for Formula (lb) are the same as those defined lor Formula
(I ) above, such as for example the functional moieties on the R2 group having an ionizablc
hydrogen with a pKa of 10 or less. Suitably such functional groups include, but arc not
limited to. hydroxy, carboxylic acid, thiol. -NH-C(0)R a . -C(0)NR6R7- substituted
sulfonamides of the formula -NHS(0) 2 Rb. -S(0) 2 NHR c . NHC(X 2 )NHRb. or tcira/.oyl (as
defined lor Formula (I)
Suitably lor compounds of Formula fib), a preferred ring substitution lor R 1 is in the
3-position. the 4- position or is preferably di substituted in the 3.4- position. The substitucnt
group is suitably an electron withdrawing moiety. Preferably R | is nitro. halogen, cyano.
irifluoromcthyl group. orC{0)NR 4 R5.
While Y may be substituted in any of the 5 ring positions, preferably the nng with the
Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being
unsubstituted. If the ring is disubstnutcd. substitucnts arc preferably in the T or 3' position of
WO 96/25157
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- 22 -
a monocyclic ring. While both R i and Y can both be hydrogen, il is prefercd that at least one
of the rings be substituted, preferably both rings arc at least mono-substituted, i.e. n amd m a
each equal to 1 or more.
Suitably lor compounds of Formula (lb), Y is more preferably disubstituted halogen,
5 mono-substituted halogen, disubstituted alkoxy, mono-substituted alkoxy. methylencdioxy.
aryl, or alkyl, preferably in the 2'position or 2'.3'-position.
Another aspect of the present invention is the novel compounds of Formula (Ic). a
subset of compounds of Formula (I) useful for treating a chemokine mediated disease. This
10 invention also relates to the pharmaceutical compositions comprising a compound of Formula
(Ic) and a pharmaceuiically acceptable diluent or carrier. The compounds of Formula do arc
represented by the strucuture:
wherein
15 X is oxygen or sulfur;
X i is oxygen or sulfur:
R i is independently selected from hydrogen: halogen: nitro; cyano: halosubstituted C ]. k>
alkyl : C i . i o alkyl: C2- 1 () alkenyl: C i . i o alkoxy: halosubstituted C | . | o alkoxy: azide:
S(0)tR4: hydroxy: hydroxyC|-4alkyl: aryl: aryl C|-4 alkyl: aryloxy: aryl C|-4 alkyloxy:
20 heteroaryl: heteroarylalkyl: heterocyclic. heterocyclic | -4alkyl: heteroarylC ] .4 alkyloxy:
aryl C2-K) alkenyl: heteroaryl C2-10 alkenyl: heterocyclic C2-K) alkenyl: NR4R5: C2- 10
alkenyl C(0)NR4R5: C(0)NR4R5: C(0)NR4R 10: S(0)3H: S(0);*Rk: C | - 10 alkyl
C(0)R 1 |: C2-10 alkenyl C(0)R 1 1; C2-I0 alkenyl C(0)OR 1 1 : C(0)R 1 1 : C(0)OR 1 2 :
OC(O) R 1 1 : NR4C(0)Ri |: or two R \ moieties together may form 0-(CH2)sO- or a 5 10 d
25 mcmbered unsaturated nng:
t is 0. or an integer having a value of I or 2:
s is an integer having a value of I to 3:
R4 and R5 are independently hydrogen, optionally substituted C1.4 alkyl. optionally
substituted aryl. optionally substituted aryl C|-4alkyl. optionally substituted hetcroarvl.
30 optionally substituted heteroaryl Ci-4 alkyl. heterocyclic, heterocyclic Ci-4 alkyl. or R4
and R5 together with ihc nitrogen to which they arc attached form a 5 to 7 member nnsj
which may optionally comprise an additional hcteroatom selected from O/N/S:
Y is independently selected from halogen: nitro: cyano: halosubstituted C|-io alkyl: Ci-io
alkyl: C2-10 alkenyl: Ci-K) alkoxy: halosubsuiuted C].|() alkoxy: azide: S(0)tR4:
35 hydroxy: hydroxy Ci-4alkyl: aryl: aryl Ci-4 alkyl: aryloxy: arylCi-4 alkyloxy: heteroaryl:
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- 23 -
heicroarylalkyl: hcteroarylC i .4 alkyloxy: hcierocyclic, heterocyclic C i-4alkyl: ary] C2-10
alkenyl; heteroaryl C2- 10 alkenyl: hcierocyclic C2-K) alkenyl: NR4R5: C2-10 alkenyl
C(0)NR4R5: C(0)NR 4 R5: C(0)NR4R|(): S(0)3H: S(0) 3 R8: Ci- 10 alkyl C(0)Ri 1;
C2- 1 0 alkenyl C(0)R 1 | ; C2- 1 0 alkenyl C(0)OR 1 1 : C(0)R 1 1 : C(0)OR 12: OC(O) R\\ :
NR4C(0)R 1 1 : or two Y moieties together may form 0-(CH2) s O- or a 5 to 6 membered
unsaturated ring:
n is an integer having a value of I to 3;
m is an integer having a value of 1 to 3:
R8 is hydrogen or C 1 .4 alkyl:
R|0isC]-|0alkyl C(0)2R8:
Rl 1 is hydrogen. Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl C|-4alkyl.
optionally substituted heteroaryl, optionally substituted heteroaryICi-4alkyl, optionally
substituted heterocyclic, or optionally substituted heterocyclicC]-4alkyl;
Rl2 is hydrogen. C].]Q alkyl, optionally substituted aryl or optionally substituted arylalkyl:
provided that
when n =1 than Y is substituted in the 2- or 3- position;
when n =2 than Y is di-substituted in the 2'- 3"- position, the 2'-5'- position, the
2'-6' position, the 3'-5' or the 3 -6' position;
when b = 3 than Y is trisubstitutcd in the 2'-3'-5' or the 2'-3'-6'- positions;
further provided that
when Xi is O. m=2. R \ is 2-t-butyl. 4-meihyl. and n=3 than Y is not 2-OH.3'-t-
butyl. 5 -mcthyl:
when X| is O. m=l. R] is 4-mcthyl. and n=2 than Y is not 2-OH. 5-methyl:
when X| is O. m=l. R] is hydrogen, and n=2 than Y is not 2'-6'-diethyl:
when X] is O. m = l. R] is 6-OH. and n=2 than Y is not 2 -5- methyl:
when X 1 is S. m=l. R| is 4-ethyl. and n= I than Y is not 2-mclhoxy:
or a pharmaceuiically acceptably saJt thereof.
Suitably, the variables, etc. for Formula (Ic) arc the same as those defined for Formula
(I) above unless indicated. .
Suitably for compounds of Formula (Io. a preferred ring substitution for R 1 is in the
3-position. the 4- position or di substituted in the 3.4- position. Preferably R| is other than
hydrogen. The substiiucnt group is suitably an electron withdrawing moiety. Preferably R| is
nitro. halogen, cyano. trilluoromelhyl group, or C(0)NR4R5.
While Y may be substituted in any of the 5 ring positions, preferably the ring with the
Y moiety is mono-substituted in the 2-position or 3- position, with the 4- preferably being
WO 96/25157
PCT/US96/02260
- 24 -
unsubstituted. II the ring is disubstitutcd, suhsiiiuents are preferably in the 2' or 3' position of
a monocyclic ring. While both R \ and Y can bolh be hydrogen, it is prclercd that at least one
of the rings be substituted, preferably both rings are at least mono-substituted, i.e. n amd m arc
each equal to I or more.
5 Suitably for compounds of Formula (Ic), Y is more preferably a mono-substituted
halogen, disubstitutcd halogen, mono-substituted alkoxy, disubstitutcd alkoxy,
methylenedioxy, aryi, or alkyl, preferably with these groups in the 2'posilion or 2.3-position.
Exemplified compounds of Formula (Ic) are:
N-|2-Hydroxy-4-(melhoxycarbonyl)phcnyI)-N'-phenylurea;
10 N-[2-Hydroxy-5-nitro-phenyl]-N'-phenyl urea
N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea
N-[2-Hydroxy-4-(trifluoromethyl)phenyl]-N'-phenyl urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-thiourea
15 N-(2-Hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-melhoxyphenyl)urea
N-(2-Hydroxy-4-nitropheny!)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-trifluoromethylphenyl)urea
20 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trinuoromethylphenyl)urea
N-(2-Hydroxy-4-nilrophenyl)-N'-(4-trinuoromethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-nhrophcnyl)-N'-(3-bromophcnyl)urea
N-(2-Hydroxy-4-niirophenyl)-N'-(4-bromophenyl)urea
25 N-(2-Hydroxy-4-nitrophcnyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-4-nilrophcnyl)-N'-(2-nitrophcnyl)urca
N-(2-HydroxY-4-nitrophenyl)-N'-(2-fluorophcnyl)urea
N-(2-Hydroxy-4-nitrophcnyl)-NW2.6-difluorophcnyl)urca
N-(2-Hydroxy-4-mirophcnyl)-N'-(2-cihoxyphcnyl)urea
30 N-(2-Hydroxy-4-mirophenyl)-N'-(2-cthyiphcnvl )urca
N-( 2- Hydroxy -4-nHrophcnyl)-N'-(2-trifluoromcthoxyphenyl)urea
N-(2-Hydroxy-4-nilrophenyl) N'-(2-mclhyllhiophcnyl) urea
N-(2-Hydroxy-4-nitro-phcnyl) N'-(2-chloro 6-mclhyl phenyl) urea
N-(2-Hydroxy-4-nitro-phenyl) N'-(2-sulfoxymcthyl phenyl) urea
35 N-(2-Hydroxy-4-irinuoromethyl phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-trinuoromethyl phenyl)-N'-(2-phenyl phenyl) urea
N-(2-Hydroxy-4-carbomelhoxy phenyl)-N' ( 2-phenyl phenyl) urea
N-l2-Hydroxy-4-nitrophcnyl)-N'-(2.3-dichloro phenyl) urea
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N-(2-Hydroxy-4-nitrophenyI)-N'-(2.4-dichloro phenyl) urea
N-(2-Hydroxy-4-nilrophenyl)-N'-(2-chloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,4-dibrorno phenyl) urea
N-(2-Hydroxy- l-napthyl)-N'-(2-bromo phenyl) urea
5 N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea
N-(2-Hydroxy-4-niirophenyl) N'-(3-chloro 2-methoxy phenyl) urea
N-[2-Hydroxy-4-(Benzylamino)carbonyl phenyl ]-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-nitro phenyl)-N'-(2-phenoxy phenyl) urea
N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea
10 N-(2-Hydroxy-3,4-difluoro phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-methyl phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-nitro phenyl)-N'-(2-phenylamino phenyl) urea
N-(2-Hydroxy 3-carboxyphenyl)-N'-(2-bromo phenyl) urea
15 N-(2-Sulfhydryl-4-bromo phenyl)-N"-(2-bromo phenyl) urea
N-(2-Hydroxy 4-nitro phenyl)-N'-(2-iodo phenyl) urea
N-(2-Hydroxy 4-niiro phenyl)-N -(2-bromo phenyl) thiourea
N-(2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea
N-f 2-Hydroxy-5-cyanophenyl]-N'-[ 2-bromophenyl] urea
20 N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromophenyl] urea
N-f 2-Hydroxy-3-fluoro-5-bromophenyl]-N'-f 2-bromophenyl] urea
N-[2-Hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-trinuoromethylphenyl]-N'-[2-bromophenyl| urea
N-[2-hydroxy-3.4-diphenyl phenyl]-N'-|2-bromophenyl] urea
25 N-f2-Hydroxy-3-glyeinemethylestercarbonylphenyl]-N , -[2-bromopheny]) urea
N-f2-Hydroxy-3-glycincarbonylphenyl]-N'-[2-bromophenylj urea
N-f2-Hydroxy-3.5-dichlorophenyl]-N'-|2-bromophenyl] urea
N-f2-Hydroxy-3-niirophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3.4-dichlorophenyl|-N'-[2-bromophenyl] urea
30 N-[2-Hydroxy-3-cyanophenyl]-N'-(2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyll-N'-f 2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl|-N'-|4-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyll-N'-[2-phenylphenyl] urea
N-|2-Hydroxy-4-cyanophenyl]-N'-[2-mcihylphenyl] urea
35 N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trinuoromethylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[3-trinuoromethylphenyl] urea
N-(2-Hydroxy-4-cyanophenyl]-N'-|4-irinuoromethylphenyl] urea
N-f2-Hydroxy-3-n-propylphenyl]-N'-[ 2-bromophenyl] urea
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N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromophenyl| urea
N-[2-Hydroxy-3-pheny]aminocarbonyl phenyl]-N'-|2-bromophenyl) urea
N-[2-Hydroxy-3-cyano-4-methylpheny] |-N'-f 2-bromophenyI | urea
N-[2-Hydroxy-4-carbopheny] phenyll-N'-^-bromophenyll urea
5 N-|2-Hydroxy-3-carbophenyl phenyl )-N'-[2-bromophenyl) urea
N-[2-Hydroxy-3-benzyloxy phenyl]-N'-[2-bromophenyl] urea
(E)-N-[4-[2-(Methoxycarbonyl) ethenylj-2-hydroxyphenyl|-N'-(2-bromophcny] | urea
(E)-N-[3-[2-(Methoxycarbonyl)elhenyI]-2-hydroxyphenyl]-N'-[2-bromopheny]|urca-N- [2-
bromophenyl] urea
10 (E)-N-[3-f2-(Aminocarbonyl)elhenyl]-2-hydroxypheny]]-N , -f2-brumophenyl|urea-N-[2-
bromophenyl] urea
(E)-N-[4-[2-(Aminocarbonyl)elhenyl]-2-hydroxyphenylJ-N'-f2-bromopheny]|urea-\-|2-
bromophenyl] urea
N-[2-Hydroxy-4-benzamide phenyl]-N'-[2-bromophenyl] urea
15 N-[2-Hydroxy-4-aminocarbonyl phenyl]-N'-[2-bromophenyl] urea
N-(2-Hydroxy-3,5,6-trifluorophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea
20 N-[2-Hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea
N-f2-Hydroxy-4-cyanophenyI]-N'-[3-methoxyphenyl | urea
N-[2-Hydroxy-5-nuorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-5-trinuoromethylphenyl]-N'-I2-bromophenylj urea
25 N-[2-Hydroxyphenyl]-N'-[2-bromophenyl] urea
N-fTrans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyll urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-[2-meihoxypheny]| urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-|4-methoxyphcnyl | urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea
30 N-[2-Hydroxy-3.4-dichlorophenyl)-N'-[2-phenylphenyl) urea
N-f2-Hydroxy-3.4-dichlorophenyl]-N -[4-phenylphenylJ urea
N-[2-Hydroxy-3.4-dichlorophenyl]-N'-[2.3-dichlorophenyl] urea
N-[2-Hydroxy-4-isopropylphenyll-N'-[3-trinuoromeihylphcnyl| urea
N- [ 2-Hydroxy-3-naphthyl |-N'-[ 2.3-dichlorophenyl] urea
35 N-(2-Hydn)xy-4-azidophenyl)-N'-(2-iodophenyl)urea
N-(2-Hydroxy-3-azidophenyl)-N'-(2-bromophenynurea
N-f2-Hydroxy-3-cyanophenyl]-N'-f2-methoxyphenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N , -[3-trinuoromethylphenyl] urea
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N-[2-Hydroxy-3-cyanophenyl|-N'-[2-phcnylphenyl | urea
N-[2-Hydroxy-3-cyanopheny]]-N , -|2.3-dichloropheny]| urea
N-f2-Hydroxy-4-isopropylpheny])-N'-f2,3-dichiorophcnyl) urea
N-f2-Hydrox y -4-isopropylphenyl]-N'-(2-chl()ro-5-trinuoromcihylphcnyI|urca
N-[2-Hydroxy-3-phenylpheny]]-N'-[2,3-dichlorophcnylj urea
N-[2-Hydroxy-5-nitrophenyl]-N , -[2-methoxyphenyl| urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[3-trifluoromethylphenyl| urea
N-[2-Hydroxy-5-nitrophenyl]-N , -[2-pheny]phenylj urea
N-f2-Hydroxy-5-nitrophenyl]-N , -f2,3-dichlorophenyl] urea
N-[2-Hydroxy-5-elhylsulfonylphenylJ-N'-[2,3-dichlorophenyl| urea
N-[2-Hydroxy-3,4-dichlorophcnyl]-N'-[2,4 dimethoxyphenyl) urea
N-[2-Hydroxy-3,4-dichlorophenyl]-NW2-chJoro-5-trifluor»meihy]phcnyl)urca
N-[2-Hydroxy-3,4-dichJoropheny]]-N'-f benzyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[3-trinuoromethylpheny]|urca
N-[2-Hydroxy-3-naphthyl]-N'-[3-trinuoromelhylphenyl| urea
N-[2-Hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-3-naphthyl]-N'-[ benzyl] urea
N-[2-hydroxy-3-(phenylaminocarbonyl) phenylJ-N'-f benzoyl) urea
N-[2-Hydroxy-3-trinuoromethylphenyl]-N , -[benzoyl] urea
N-f2-Hydroxy-4-cyanophenyl]-N-fbenzoyl] urea
N-f 2-Hydroxy-5-naphthalenesulfonic acid]-N'-[2-bromopheny 1 1 urea:
N-[2-Hydroxy-4-naphthalcnesullonic acid]-N-( 2-bromophcny] | urea;
N-(2-Hydroxy 3-napihyl) N , -(2-bromo phenyl) urea:
N-(2-Hydroxy-l-napthyl)-N'-(2-bromo phenyl) urea:
N-(2-Hydroxy-4-mtrophenyl)-N'-( 1 -naphthyDurea:
Suitable pharmaceutical^ acceptable salts are well known to those skilled ,n the art and
include basic salts of inorganic and organic adds, such as hydrochloric acid, hvdrobromic
acd. sulphuric acid, phosphonc acid, methane sulphon.c acid, ethane sulphonic acid acetic
acid, mal.c acid, tanaric acid, citric acid, lactic acid, oxal.c acd. succ.n.c acd. .umanc acd
maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandclic acid. In addition
pharmaceutically acceptable sails of compounds of Formula (I) mav also be formed with a
pharmaceutical^ acceptable canon, for instance. ,1 a substiiueni group emprises a carboxy
mo.ciy. Suitable pharmaceutically acceptable cations are well known to those skilled in the art
and include alkaline, alkaline earth, ammonium and quaternary ammonium cations
The following terms, as used herein, refer to.
• "halo" - all halogens, that is chloro. fluoro. bromo and lodo.
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• "C].|()alkyl" or "alky!" - both straight and branched chain radicals of I to 10 carbon
atoms, unless the chain length is otherwise limited, including, but not limited to. methyl, ethyl.
/7-propyl. i.s-fj-propyl, n-bulyl, .vf c-butyl. /.vo-butyl. /m-butyl. /7-pentyl and the like.
• The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8
carbons, including but not limited to cyclopropyl. cyclopentyl. cyclohexyl. and the like.
• The term "alkenyl" is used herein at all occurrences to mean straight or branched
chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not
limited to cthenyl, 1-propenyl. 2-propenyl. 2-mcihyl- 1 -propenyl. 1-butenyl, 2-butcnyl and the
like.
• "an 1" - phenyl and naphthyl,
• "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or
"heteroaryl alkyl") - a 5-10 membered aromatic ring system in which one or more rings contain
one or more heieroaioms selected from the group consisting of N. O or S. such as. hut not
limited, to pyrrole, pyrazole. furan. thiophene. quinolinc. isoquinolinc. quinazolinyl. pyridine,
pyrimidine, oxazole, thiazolc, thiadiazolc. triazole, imidazole, or benzimidazolc.
• "heterocyclic" (on its own or in any combination, such as "hctcrocyclicalkyl") - a
saturated or partially unsaturated 4- 10 membered ring system in which one or more rings
contain one or more heteroaloms selected from the group consisting of N. O, or S: such as. but
not limited to. pyrrolidine, piperidine, piperazine. morpholine, tetrahydropyran. or
imidazolidine.
• The term "arylalkyl" or "heteroarylalkyl" or "hetcrocyclicalkyl" is used herein to
mean C i - K) alkyl. as defined above, attached to an aryl. heteroaryl or heterocyclic moiety, as
also defined herein, unless otherwise indicated.
• "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio" relcrs to the
sulfide, and the term "sulfonyl" refers to the fully oxidized S(0)2 moiety
• The term "wherein two R i moieties (or two Y moieties) may together lomi a 5 or 6
membered unsaturated ring" is used herein to mean the formation of a naplhylcne ring system
or a phenyl moiety having attached a 6 membered partially unsaturated ring such as a
cycloalkcnyl. i.e hexenc. or a C5 cyloalkenyl moiety . cyclopcntenc.
The compounds of Formula (I). (Ia), (lb). (lc). (II) and (III) may be obtained by
applying synthetic procedures, some of which are illustrated in the Schemes below. The
synthesis provided lor in these Schemes is applicable for the producing compounds of Formula
(I), da). (II) and (III) having a variety of different R. R |. and Ar groups which are reacted,
employing optional subsutucnts which arc suitably protected, to achieve compatibility with the
reactions outlined herein. Subsequent deprotection. in those cases, then affords compounds of
the nature generally disclosed. Once the urea nucleus has been established, further compounds
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of these formulas may be prepared by applying standard techniques for functional group
intercon version, well known in the an. While the schemes arc shown with compounds only of
Formula (I) this is merely for illustration purposes only.
Scheme 1
1 2
R=NH 2 , OH, C0 2 H, SH a)PhNCO
NHSQ 2 R
Ortho substituted phenyl ureas shown in 2-scheme 1 may be prepared by standard
conditions involving the condensation of commercially available ortho substituted
aniline(Aldrich Chemical Co.. Milwaukee, Wi) with the commercially available optionally
substituted aryl isocyanatc (Aldrich Chemical Co., Milwaukee, Wi) in an aprouc solvent
(DMF, toluene). When the l-(RS02NH)2-(NH 2 )Ph is not commercially available it can be
made by treating the commercially available RSO2CI with the cooresponding 2-phenylene
diamine in the presence of an base like methyl amine or NaH in an aprouc solvent (like
methylene chloride or DMF).
Scheme 2
2 4 5
R"=OH. NH 2 . NHS0 2 R a)HN0 3 . 23 "C b)SnCI 2 . EtOH
If the desired 2-.substitutcd aniline 5-schemc 2 . is not commercially available the
corresponding nitro compound can be prepared from 3-schp.mp ? under standard nitration
conditions (using HNCh or BF4NQ3) at 23 °C. The nitro compound is then reduced to the
corresponding aniline using SnCh in EtOH(or alternately Fb/Pd or LiAlFLj).
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Scheme 3
£2 fi
a) NH 4 SCN. Br 2
b) NaOH EtOH
II the desired 2-amino bcnzcnelhiol K-sehemc 3 is not commercially available ii can be
synthesized by reaction of the phenyl aniline with the thiocyanate anion in the presence of an
oxidanUlike bromine) to produce the 2-amino benzthiazole 7-scheme 3 . This thiazole can then
be hydrolyzed to the desired 2-amino benzenethiol 8 -scheme 3 with a strong base like NaOH in
a protic solvent (i.e., EtOH).
Scheme 4
a)TBSCl. imid. DMF b)i)CICXCI, NaHC0 3 . ii)PhNH 2 c)Et 3 N»HF. CH 3 CN
In the case where the thioisocyanate or phenyl isocyanate is not commercially
available, the thiourea or urea 1 1 -scheme 4 may be prepared from the commercially available
ortho substituted aniline This compound is first protected with a protecting group (ten-butyl
dimethyl silyl or benzyl ) by conditions well known in the arKsec Greene. T Protecting
Groups in Organic Synthesis . Wiley&Sons. New York. 1981). This protected aniline is then
reacted, in the presence of a base(likc triethyl amine or sodium bicarbonate), with either
thiophosgene or a solution of phosgene in an aprolic solvent (ie. DMF. toluene), followed by
aniline to produce the protected thiourea or urea respectively. The corresponding urea or
thiourea is then dcprotecied. using conditions standard in the art. to form the desired thiourea
or urea 1 1 -scheme 4.
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Scheme 5
a
12
C0 2 H
a. b
a)(PhO) 2 PON 3 ,Et 3 N b)PhXNH 2
X=OH. NHS0 2 R, SH
Alternately the urea can be formed using a Curtius rearrangement from the
corresponding aromatic or thiophene carboxylic acid 12-scheme 5 The carboxylic acid is
submitted to standard Curtius conditions ((PhOtePON-*, Et3N or C1COCOC1 followed by
5 NaN3) and the intermediate isocyanate is trapped by an appropriately substituted aniline.
Pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in
known manner, for example by treatment thereof with an appropriate amount of acid or base in
the presence of a suitable solvent.
Another aspect of the present invention is the novel synthesis of cyano nitrophenol
intermediates. Numerous conversions of aryl halides to aryl cyano derivatives with copper (I)
cyanide have been published. However, no examples of an aryl ring with a hydroxy group
present were mentioned. Several attempts to obtain a cyano phenol moiety with published
1 5 results failed. Using known conditions of elevated temperatures, greater than 1 70°C. such as
from 1 80 to 2 1 0' did not yield displacement of the halogen to a cyano moiety. Standard bases,
such as DMF and pyridine further provided no desired product. Intermediates such as 2-
amino-5-fluorophenol. 2-nitro-5-fluorophenol, 2-nitro-5-methyl-6-bromophenol were incd
with a change of halogens, from fluorine to chlorine to bromine, and with use of copper (D
20 cyanide. The use of a bromine derivative, such as 2-nitro-5-methyl-6-bromopheno] . with
dimethylformamide and using triethylamine with a catalytic amount of dimelhylamino pyridine
and copper (I) cyanide at reduced temperatures,, i.e. <l(Xrc. preferably 60 to about 80 C lor
reduced times from strandarized procedures, i.e., < 18 hours, preferably about 4 to 6 hours
yielded the desired products.
25 Therefore one aspect of the invention is to a process for producing a cyano phenol
derivative of the formula:
10
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X
wherein R\ is as defined for Formula (I) above, which method
comprises reacting a compound of the formula:
OH
-T-X
Rl wherein X is halogen with copper (I) cyanide, dimethyllormamidc.
triethylamine and a catalytic amount of dimethylamino pyridine. Preferably, the process is run
5 at reduced temperatures of about 60 to about 80°C. Preferably X is bromine.
In the Examples, all temperatures are in degrees Cenugrade (°C). Mass spectra were
performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise
indicated. 1 H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz or 400MHz
10 using a Bruker AM 250 or Am 400 spectrometer, respectively. Multiplicities indicated arc:
s=singlet. d=doublet, t=triplei, q=quartet, m=multiplet and br indicates a broad signal. Sat.
indicates a saturated solution, equiv. indicates the proportion of a molar equivalent of reagent
relative to the principal reactant.
Flash chromatography is run over Merck Silica gel 60 (230 - 400 mesh)
15
SYNTHETIC EXAMPLES
The invention will now be described by reference to the following examples which arc
merely illustrative and are not to be construed as a limitation of the scope of the present
invention. All temperatures are given in degrees centigrade, all solvents used herein are of the
20 highest available purity and all reactions are run under anhydrous conditions in an argon
atmosphere unless otherwise indicated.
General Method A: Synthesis of N, N'- phenyl urea To a solution of substituted
phenyl isocyanate (l.Oequiv.) in toluene (5 miliLitcrs (hereinafter "mL")) the corresponding
25 aniline ( 1 .0 equiv.) was added. The reaction mixture was stirred at about X0°C until complete
(24-48 hours (hereinafter "hrs" or "h")). then cooled to room temperature. The purifications,
yields and spectral characteristics for each individual compound are listed below
30
General Method B: Synthesis of N, N'- phenyl urea To a solution of phenyl
isocyanate (l.Oequiv.) in dimethyl formamide (lmL) the corresponding aniline (l.Oequiv.)
was added. The reaction mixture was stirred at about 8()°C until complete (24-4N hours), then
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the solvent was removed under vacuum. The purifications, yields and spectral characteristics
lor each individual compound are listed below.
General Method C:Synthesis of sulfonamide The ortho substituted aniline ( 1
triethyl amine (1 equiv.) and the desired sulfonyl chloride (1 equiv.) were combined i
methylene chloride and allowed to stir at about 23 °C until complete ( 1 2-36 h). The n
mixture was partitioned between water and methylene chloride. The organic layer wa
separated and dried over magnesium sulfate, filtered and concentrated in vacuo. The
purifications of each compound are listed below.
Example 1
Preparation Of N-r2-Hvdroxv-4-rmpt hoxvcarhnnvl)nhenvn-N^nhenvl nrra
N-[2-Hydroxy-4-(methoxycarbonyl)phenylJ-N'-phenyl urea was prepared from
methyl-4-amino-3-hydroxybenzoate (200 mg, 1 . 19 mmol) and phenyl isocyanate (1.19 mmo]
according to the procedure noted above in General Method A. The product was purified by
precipitation from toluene, and filtering, to afford the tided compound (309 mg, 9()<7r). mp:
1 88.4- 1 88.8°C: 1 H NMR (CD3OD/CDCI3): 6 8.15 (d, 1H, J = 8.25 Hz). 7.70 (s, 1H), 7.51
(d, 1H, J = 8.25 Hz), 7.43 (d, 2H, J = 8.25 Hz), 7.30 (t, 2H, J = 8.25 Hz), 7.01 (t. IH. J -
8.25 Hz), 3.87 (s, 3H); EI-MS m/z 286 (M+H) + : Anal. (C15H14N2O4) C. H, N.
Examnle 2
Preparation of N-f5-nitro-2-hvri mxvnhenvll-N'-phenvl urea
The N-[5-nitro-2-hydroxyphenyl)-N'-phenyl urea was prepared from the 5-nitro 2
hydroxy aniline and phenyl isocyanate according to the procedure in General Method A. The
product was purified by precipitation from toluene and filtering to afford the titled compound
(100 mg. 307,). 1H NMR (CD3OD): 8 9.48 (s. IH. NH). 9.07 (d. .1 = 1.56 Hz. NH). 8.55
(s. IH), 7.80 (dd. 1 H. .1 = 6.25 Hz and J = 1.56 Hz). 7.50 (d. 2H. J = 6.25 Hz). 7.30 (t. 2H
J = 6.25 Hz), 7.01 (m. 2H). EI-MS m/z 273 (M+H)+.
Example 3
Preparation of 3-hvdr oxv-4-(f(nhenvlamino)carhonvllaminolheny;imiMe
a) Prcparation of 0.67 Molar (hereinafter "M") Stock Solutions of Aluminum Amide Reagents
To a suspension of the appropriate hydrochloride (0.02 mole (hereinafter "mol")) m ur\
toluene (20 mL) at about 0°C, was slowly added a solution of (2M. 10 mL) of tnmethvl
aluminum in toluene. Alter the addition was complete, the reaction mixture was allowed to
warm to room temperature and was stirred for about 1-2 hours until gas evolution has ceased
b) Preparauon of 3-hydroxy-4-{[(phenylamino)carbonyl]amino)bcnzamide
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To a solution of the N-[2-hydroxy-4-(mcthoxycarbonyl)phcny] |-N'-phenyl urea (60
miligram (hereinafter "mg"), 0.2 mmol) in toluene (2 mLj was added aluminum amide reageni
(0.9 mL, 0.67M). The reaction mixture was stirred at reflux for about 12 hours. The reaction
mixture was cooled to room temperature and was carefully quenched with 5% HC1. The
organic layer was separated and the aqueous layer was extracted three limes with ethyl acetate.
The organic extracts were combined, dried over MgSC>4, filtered and concentrated under
reduced pressure. Chromatography of the resulting solid on silica gel (ethvl acetate) gave the
desired amide (28 mg. 497r). mp: 106.8- 107. 1°C: >H NMR (CD^OD/CDC^): 5 7.98 (d, 1H.
J = 8.25 Hz), 7.35 (d, 2H, J = 8.25 Hz), 7.30 (d, 2H, J = 8.25 Hz). 7 17 (t, 2H. J = 8.25
Hz). 6.91 (t, 1H, J = 8.25 Hz); EI-MS m/z 271 (M+H) + : Anal. (C14H13N3O3) C. H. N.
Example 4
Preparation of N-f2-hvdroxv-4-nuo ronhenv11-N'-nhenvl urea
a) Preparation of 2-amino-5-fluoro phenol
A mixture of 5-fluoro-2-nitrophenol (5(K) mg, 3. 18 mmol) and tin (II) chloride (1 .76
g, 9.2 mmol) in ethanol ( 10 mL) was heated at 80°C under argon. After 30 min. the starting
material had disappeared and the solution was allowed to cool down and then poured into ice.
The pH was made slightly basic (pH 7-8), by addition of 57c aqueous sodium bicarbonate,
before being extracted with ethyl acetate. The organic phase was washed with brine, dried over
MgSC»4and filtered. Evaporation of the solvent gave the title compound(335 mg, 83%). 'H
NMR (CD ? OD/CDCh): 6 6.6 (m. IH), 6.38 (dd, IH, J = 8.3 Hz and .1 = 2.8 Hz). 6.29 (m.
1H).
b) Preparation of N-(2-hydroxy-4-f1uorophenyl)-N'-phcnyl urea
N-(2-Hydroxy-4-nuorophcnyl)-N -phcnyl urea was prepared l mm 2-amino-5-fluoro
phenol (200 mg. 1.57 mmol) and phenyl isocyanatc according 10 the procedure in General
Method A. The product was purified by precipitation from toluene and filtering to afford the
titled compound (352 mg. 91 <7<). mp: 195.5- 195. 7°C: 'H NMR (CDiOD/CDCh): 8 7.70 (m.
IH), 7.3 (d. 2H. J = 8.25 Hz). 7.15 (t. 2H. J = 8.25 Hz). 6.K9 (i. IH. .1 = 8.25 Hz). 6.50 -
6.38 <m. 2H): EI-MS m/z 246 (M+H) + : Anal. (CnHj 1N2O2 F) C. H. N.
Example 5
Preparation of 2- ( liphenvlamino (carbon vl lamino Uhiophcnol
2-{|{Phenylamino)carbon\i|amino}lhiophcnol was prepared from 2-aminothiophenol
(2(K) mg. 1.6 mmol) and phenyl isocyanatc according 10 the procedure in General Method A
The product was purified by precipitation from toluene and filtering to afford the titled
compound (330 mg. 85 7c). mp: 194. 5°C; *H NMR (CD^OD/CDCh): 6 7 48 - 7.26 <m. 4H).
7.25 - 7.10 (m. 3H). 7.04 - 6.79 ym. 2H); EI-MS m/z 244 (M+Hi»: Anal. (C13H12N2OS) C.
H. N.
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Example 6
Preparation of N-r2-Carhoxv-4-hvrim X vnhflnvh-NI '-nhcnvl nn».j .
N-(2-Carboxy-4-hydroxyphenyl)-N'-phcnyl urea was prepared from 2-amino-5-
hydroxy benzoic acid ( 1 g, 6.53 mmol) according to the procedure in General Method B The
reaction mixture was partitioned between ethyl acetate and water. The organic phase was
washed with bnne, dried over MgS0 4 and filtered. Removal of solvent under reduced pressure
and chromatography of the resulting solid on silica gel (hexane : ethyl acetate 1 ■ 1 to 1 00*
ethyl acetate) gave the titled compound ( 1 .5 g. 84* ). l H NMR (CD,OD/CDCl 3 )- 6 8 36 (d
1H, J = 8.25 Hz), 7.63 (m. 4H). 7.48 (t, 2H. J = 8.25 Hz). 7.20 (m, 1H): EI-MS m/z 27^ '
(M+H) + : Anal. (C14H12N2O4) C. H, N.
Example 7
Preparation of N - \2 - hydroxy - 4- Oriflnnmm^ h vh phenyl) . nt . nhen^ „ rpfl
a) Preparation of 2-nitro-5-trinuoromethylphenol
2-Nitro-5-trinuoromethylphenol was prepared by adding concentrated HNO3 (6 mL)
drop-wise to a.a.oc-trifluoro-m-cresol (5g, 30.8 mmol) at room temperature. After the
addition was complete the reaction was quenched with saturated ammonium acetate and
extracted with EtOAc. The organic was separated, dried over sodium sulfate and filtered
Concentration of the solution in vacuo afforded an oil which was purified by column
chromatography (gradient 100* hexane to 50* EtOAc/hexanes) to afford the titled compound
asano.Kl.7g. 27* >. IH NMR (CDCl.,): 10.6 (s. I H. OH). 8.26(d. IH. J = 7.8 Hz).
7.45(s. 1H. arom). 7.26(d. IH. J= 7.8 Hz)
b) Prcparalion of 2-amino-5-trifluoromcihylphenol
2-Amino-5-tnnuoromethylphenol was prepared hv treating 2-niiro-5-
trilluoromethylphenol (5(H) mg. 2.41 mmol) with a soluhon of SnCI 2 (3.5g. mmol) in ElOH at
23 °C for 12h. The mixture was concentrated u, 50 mL and adjusted 10 P H 7 using saturated
sodium bicarbonate. The reaction mixture was partitioned between H 2 0 and EtOAc. The
aqueous layer was separated and extracted with EiOAc. The combined oreanic extracts were
dried over sodium sulfate, filtered and concentrated m vacuo. The resulting colorless oil(37()
my. 87*?? ) was used without further purification. IH NMR (CDCh): 7.6 (s. IH). 7 39(d
1 H. .1 - 8.5 Hz). 7.08(d. IH. J= 8.5 Hz) '
Preparation of N - |2 - hydroxy - 4- (influoromethyl) phenyl) - N" - phenyl urea
N - [2 - Hydroxy - 4- (trifluoromcthyl ) phenyl | - N" - phenyl urea was prepared from
2-amino-5-inlluoromcihylphenol (150 mg. l.oy mmol) and phenyl isocyanatc( 1 .09 mmol)
according to the procedure in General method A The product was purified by precipitation
from methylene chloride and filtering to afford the tilled compound ( 230 m o 87* , mp- °C
1HNMR (DMSO-d 6 ): 5 9.45 (s. IH. NH). 8.50 (s. 1H.NH).8.31 (d IH J= 100 Hz,
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7.45 (d, 2H. J = 10.0 Hz). 7.29 (t. 2H. .1 = 6.67 Hz). 7.10 (m. 2H). 6.99 (I. 1H, J = 6.67
Hz) EI-MS m/z 296 (M + ). Anal. (CiaHn^CHF^C, H, N.
Example 8
5 Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea
a) Preparation of 2-(/m-butyldimeihylsilyloxy)-4-nitroaniline
To a solution of 2-amino-5-nitrophenol (1 g, 6.49 mmol) and imidazole (0.88 g. 12.3
mmol) in DMF ( 1 5 mL), ten -butyldimeihylsilyl chloride ( 1 1 .2 mL, 64.9 mmol) was added.
10 The resulting mixture was allowed to stir at 23°C for 48 hours. The reaction mixture was
partitioned between 0. 1 % HC1 and ethyl acetate. The combined organic phase was washed
with brine, dried over MgSOa and filtered. Removal of solvent at reduced pressure and
chromatography of the resulting oil on silica gel (hexane : ethyl acetate: 5: 1 ) gave the titled
compound (1.7 g. 98 9c). 'H NMR (CDCI3): S 7.78 (dd, 1H, J = 6.7 Hz and J = 2.7 Hz).
IS 7.61 (d, 1H, J = 2.7 Hz), 6.7 (d, 1H, J = 8.8 Hz), 1.0 (s, 9H). 0.28 (s. 6H).
b) Preparation of N-[(2-/fr/-butyldimethylsilyloxy)-4-nitrophenyl]-N'-|(2-tert-
buiyldimethylsiloxy)-4- nitrophenyl] urea
To a solution of 2-(ieri-butyldimethylsilyloxy)-4-nitroaniline(200 mg, 0.75 mmol) in
toluene ( 10 mL) tricthylamine (0.13 mL, 1.64 mmol) and triphosgenc (88 4 mg, 0.3 mmol)
20 were added. The reaction mixture was stirred at 70°C for 2 hours, then cooled to room
temperature. Then more 2-(tert -butyldimethylsilyloxy)-4-nitroanilinc (2(X) mg, 0.75 mmol)
was added. The resulting mixture was allowed to sur at 70°C for 48 hours then cooled to room
temperature. The reaction mixture was partitioned between water and ethyl acetate. The
combined organic phase was washed with brine, dried over MgSOa and filtered. Removal 01
25 solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexanc : ethyl
acetate. 10:1) gave the tilled compounds 30 mg. 31*). >H NMR (CDC1V): 5 8.36 (d. 2H. .1 =
8.3 Hz). 7.90 (dd. 2H. J = 8.3 Hz and J = 2.8 Hz). 7.71 (d. 2H. J = 2.8 Hz). 7.22 (s. 2H).
1.02 (s. 18H). 0.35 (s. 12H).
c) Preparation of N-(2-Hydroxy-4-niirophcnyl)-N'-(2-hydroxy-4-mtrophenyl) urea
30 To a solution of N-i(2-terl-butyldimethylsilyloxy)-4-nilrophcnyl]-N'-l(2-ierl-
butyldimethylsilyloxy)-4- nitrophenyl| urca(50 mg. 0.089 mmol) in THF (2 mL).
icirabutylammonuim lluoridc (1 M. 0.09 mL. 0.089 mmol) was added at 0°C. The reaction
mixture was stirred at 23°C. After 1 hour, the starling material had disappeared. The reaction
mixture was partitioned between water and ethyl acetate. The combined organic phase was
35 dried over MgSOa and filtered. Removal of solvent at reduced pressure and chromatography oi
the resulting oil on silica gel (hexanc : ethyl acetate: 1:1 to 100% ethyl acetate) gave the titled
compound(24 mg. 81*8). 'H NMR (CDiOD/CDCh): 5 8.32 (d. 2H. J = 8.25 Hz). 7.80 (dd.
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2H, J = 8.25 Hz and J = 2.06 Hz). 7.7 (d, 2H, J = 2.06 Hz). EI-MS m/z 334 (M+H)+ Anal
(CnH|()N 4 07) C, H, N.
Example Q
Preparation of N-(2-hvdroxv-4-nitm p hPnvn-N'-ph P nyi.^p vrn
a)Prcparai]onorN-(2-tcrt-butyldimeihysilyloxy-4-nitrophenyl)-N'-phenyl-ih]ourea
N-(2-tcrt-Butyldimethy.silyloxy-4-nitrophenyl)-N'-phenyl-thiourca was prepared by
treating a biphasic soluuon of 2-tert-butyldimethysilyloxy-4-nitroaniline(80 mg, 0 308 mmol)
and NaHCO ? .n CHC1 3 :H 2 0(2.5: 1 , 7mL) with thiophosgene at 0°C. The soluuon was allowed
to warm to 23°C and the reaction was continued overnight. The CHCI, layer was separated
and dried over sodium sulfate. The solution was concentrated in vacuo and the residue was
dissolved in toluene and treated with anilme (100 uL) at 23 °C for 12 h. The reaction mixture
was concentrated and the residue was purified by flash chromatography (10% EtOAc/hexanes)
to afford the titled compound as a yellow solid (120.8 mg, 98%) mp- 144-145°CMH NMR
(CD3OD/CDCI3): 5 8.65 (d, 1H, J = 10.0 Hz), 7.58 (d, 1H, J = 10.0 Hz), 7.47 (d. IH. J =
1.25 Hz), 7.26 (m. 4H), 7.10 (m, 1H).
MPrcparaiion of N-(2-hydroxy-4-nitrophenyl)-N , -phenyl-thiourea
N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-2-ihiourea was prepared by treating a
solution or N-(2-ten-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea (100 mg 0 248
mmol) in CHjCN ( 1 mL) with Et^N-HF (lOOuL, 0.62 mmol) in aceioniirile for 10 minutes at
23°C. The soluiion was concentrated and flushed through a silica plug with EtOAc to afford
the desired compound as an orange solid (55 mg, 77%).
mp: l44-145°C:'HNMR(CD 3 OD/CDCl3):5 8.65 (d. 1H, J = 10.0 Hz). 7.58 (d. IH.J =
10.0 Hz). 7.47 (d. 1H. .1 = 1.25 Hz), 7.26 (m. 4H). 7.10 (m. 1H).
Example 10
Preparation of N-f4- nitro 2-(nhenvk.ilfn nvlaminnlphn n vn-N'-ph P nvl ,,nv.
a) Preparation of 4-nitro 2-(phcnylsulfonylamino) aniline
A solution of 4-nitro 1.2-phcnylcne diamine* 1.53 g. 10.0 mmol ) in DMF was treated
with phenyl sullonyl ehlonde(1.76 g. 10.0 mmol) and tnethyl amine( 1.01 g) ,n DMF for 12 h
al 23 "C. The reaction mixture was partitioned between saturated NH 4 C1 and methylene
chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
The resulting solid was rccrystallized (EtOH) to afford desired (0.275 g. ). 'h
NMR(DMSO) 9.5(s. 1H. hr). 7.83 (dd. 1H. J=l() Hz. 2 Hz). 7.74(d.^H. J=8 Hz) 7 76(1
IH..I=8Hz). 7.56(1. 2H.. 1=8 Hz). 7.55(d.lH. J=2Hz). 6.79 (d. 1H. J=8Hz) 6 5(s ?H '
br)
b) Preparaiion of N-(4- nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea
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N-(4-Nnro 2-(phenylsulfonylamino)phenyl)-N-phenyl urea was prepared lrom 4-
nitro 2-(phenylsulfonylamino) aniline(82 mg) and phenyl isocyanate(33 mg) by method A.
The reaciion was cooled and then partitioned between saturated ammonium chloride and 9: 1
methylene chloride and methanol. The organic phase was dried over magnesium sulfate.
5 filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl
acetate/hexanes) to afford desired(30.8 mg, 26%). EI-MS m/z 4 I3(M+H)*
Example 1 1
Preparation of N-(2-hvdroxv-5-nitrophenvl)-N'-(3-methoxy-2-thienvl)urea
10 a)Preparation of 3-methoxy-2-thienylcarboxlic acid
To a solution of 3-methoxythiophene (4.81 g, 42. 1 mmoll in ether (20 mL) at -78°C.
butyllithium (17 mL, 47.6 mmol) was added. The reaction mixture was stirred at -78°C for 1
hour, then it was warmed to 0°C for 3 hours. After to recooling -78°C the reaction mixture
was poured into a beaker filled with crushed dry ice (14.5 g) and allowed to stand until the
15 excess dry ice had completely sublimed. Then the reaction mixture was poured into a mixture
of ice (10 g) to which cone. HC1 (24 mL) had been added. The product was purified by
precipitation from ether and filtering (6.42 g, 96 %). EI-MS m/z 159 (M+H)\
b)Preparation of N-(2-hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thicnyl)urea
To a solution of 3-methoxy-2-thiophene carboxylic acid (200 mg. 1 .27 mmol) in
20 benzene, (PhO^PON? (0.33 mL), 2-amino-4-nitrophenol (195.7 mg. 1 .27 mmol) and
tnethylamine (1.1 equiv.. 0.25 mL) were added. The reaciion mixture was stirred at reflux
overnight. The reaction mixture was partitioned between 5% citric acid and ethyl acetate The
organic layer was separated and the aqueous layer was extracted three times with ethyl acetate
The organic extracts were combined, dried over MgS04. filtered and concentrated under
25 reduced pressure Chromatography of the resulting solid on silica gel (hexanerethy)
acetate:l:l) gave a solid product (160 mg. 41%). mp: 172.6-1 73. ()°C: 'H NMR
(CD^OD/CDCl-0: 5 8.96 (d. 1H, J = 2.5 Hz). 7.74 (dd. 1H. J =5.0 Hz and J = 1.25 H/j.
6.82 (d. 1H. J =7.5 Hz). 6.76 (s. 2H), 3.80 (s. 3H): EI-MS m/z 309 (M+H) + : Anal
(C12H11N3O.SS) C. H. N.
30
Example 12
Preparation of N-(2-hvdroxv-4-nitrophcnvl)-N'-(3-mcthoxv-2-thicnvl )urea
To a solution of 3-methoxy-2-thiophene carboxylic acid (example 1 la. 200 mg. 1 .27
mmol) in toluene. (PhO^PON} (0.33 mL) and tricthylamine (1.1 equiv.. 0.25 mL) were
35 added. The reaction mixture was stirred at 70°C for 2 hours and cooled down to room
temperature then 2-amino-5-nitrophenol was added. The reaction mixture was stirred at 70°C
overnight. The reaciion mixture was partitioned between 5% citnc acid and ethyl acetate. The
organic layer was separated and the aqueous layer was extracted three times with ethyl acetate
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The organic extracts were combined, dried over MgSCU, filtered and concentrated under
reduced pressure. Chromatography of the resulting solid on silica gel (hexane.ethyl
acetate:l:l) gave the product (190 mg, 48%). l H NMR (CD3OD/CDCI3): 6 8.38 (d. 1H, J =
5.0 Hz). 7.85 (dd. 1H, J = 5.0 Hz and J = 1.25 Hz), 7.76 <d. IH, J = 2.5 Hz), 6.9 (s, 2H).
5 3.95 (s, 3H): EI-MS m/z 309 (M+H) + : Anal. (Cj 2 Hi 1N3O5S) C, H, N.
Example 13
Preparation of N-^-hvdrnx v-^nitrophenvn-N'-n-methnxvphRnvniimM
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-
hydroxy 4-nitro aniline (154 mg. l.Ommol) and 3-methoxy phenyl isocyanate(l.() mmol)
10 according to the procedure in General Method B. The product was purified by dilution with
methylene chloride and precipitation with hexanes. Filtering afforded the title compound (140
mg, 46%). EI-MS m/z 302(M-H) -
Example 14
15 Preparation of N-f2-hvdroxv-4-nitrophenvn-NV?- methoxvphenvlWp a
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea was prepared from 2-
hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-methoxy phenyl isocyanate(l mmol.)
according to the procedure in General Method B. The product was purified by dilution with
methylene chloride and precipitation with hexanes. Filtering afforded the title compound (82
20 mg. 27%). EI-MS m/z 302(M-H)-
Examnle 15
Preparation of N-(2-hydroxv-4-nitrophcnvl)-NW3-trinuoromcthvlphcnvl )urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-
25 hydroxy 4-nitro aniline (1 54 mg, 1 .0 mmol) and 3-trifluoromelhyl phenyl isocyanate ( I mmol)
according to the procedure in General Method B. The product was purified by dilution with
methylene chloride and precipitation with hexanes. Filtering afforded the title compound (180
mg. 527. ). EI-MS m/z 342(M+H) +
Example 16
30 Preparati on of N'-f2-hydroxy-4-nitrophenvl)-N'-(2-trinuoromethvlnhenvl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromcthylphenyl)urca was prepared from 2-
hydroxy 4-nitro aniline (154 mg. 1.0 mmol) and 2-trifluoromethyl phenyl isocyanate ( 1 .0
mmol) according to the procedure in General Method B. The product was purified by dilution
with methylene chloride and precipitation with hexanes. Filtering afforded the title compound
35 ( 1 80 mg. 52<7< ). EI-MS m/z 342(M+H) +
Example 17
Preparation of N-(2-hvdroxv-4-nurophenvl)-N'-(4-trifluoromethvlphenvr)urea
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N-(2-Hydroxy-4-niirophenyl)-N'-(4-trinuoromethylphcnyl)urca was prepared from 2-
hydroxy 4-mtro aniline (154 mg, 1.0 mmol) and 4-trinuoromcthyl phenyl isocyanate (1.0
mmol) according to the procedure in General Method B. The product was purified by dilution
with methylene chloride and precipitation with hexanes. Filtering afforded the title compound
5 (1 1 1 mg, 32%). EI-MS m/z 340(M-H)-
Examnle IX
Preparation of N-(2-hvdrox v-4-nitrophenvn-N , -r2-hromonhenvnnrp.^
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea was prepared from 2-hydroxy
4-nitro aniline (5(X) mg, 3.24 mmol) and 2-bromophenyl isocyanate (3.24 mmol ) according to
10 the procedure in General Method B. The product was purified by dilution with methylene
chloride and precipitation with hexanes. Filtering afforded the title compound(53() mg, 47 )
EI-MS m/z 350(M-H) -
Example. 19
15 Preparation of N-(2-hvdroxv-4-nit ronhenvh-N , -(3-hromophenvnurea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromo phenyDurea was prepared from 2-hydroxy
4-nitro aniline (500 mg. 3.24 mmol) and 3-bromo phenyl isocyanate (3.24 mmoDaccording to
the procedure in General Method B. The product was purified by dilution with methylene
chloride and precipitation with hexanes. Filtering afforded the title compound(0.96g. Kl c 7, ).
20 EI-MS m/z 35()(M-H)-
Example 20
Preparation of N-(2-hvdroxv-4-nitrophenvlVN'-(4-hromophcnvl)urea
N-(2-Hydroxy-4-nitrophcnyl)-N'-(4-bromo phenyDurea was prepared from 2-hydrox\
25 4-nitro aniline (5(K) mg, 3.24 mmol) and 4-bromo phenyl isocyanaic (3.24 mmol) according m
the procedure in General Method B. The product was purified by dilution with methylene
chloride and precipitation with hexanes. Filtering afforded the title compound^) 4 1 g. 37<# )
EI-MS m/z 352(M+H) +
30 Example 21
Preparation of N-(2-hvdroxv-4-nitrophenvl')-N'-(2-phenvlphcnvl)urea
K-(2-Hydroxy-4-nitrophcnyl)-N'-(2-phenylphcnyl)urea was prepared from 2-hydrox>
4-nitro aniline (5(K) mg. 3.24 mmol) and 2-phcnyl phenyl isocyanate (3.24 mmol) according
to the procedure in General Method B. The product was purified by dilution with methylene
35 chloride and precipitation with hexanes. Filtering afforded the title compound(0.22 g. 19'/f )
EI-MS m/z35()(M+H) +
Example 22
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Preparation of N-(2-hvdroxv-4-mir onhenvn-N'-( l-naphihvl)u r n
N-(2-Hydroxy-4-nitrophenyl)-N'-(l-naphthyl)urea was prepared from 2-hydroxy 4-
niiro aniline (500 mg, 3.24 mmol) and 1-naphthyl isocyanate (3.24 mmol) according to the
procedure in General Method B. The product precipitated from methylene chloride and filtered
The resulting solid was titruated with 1 :3 triethyl amine:methylene chloride. The filterate was
concentrated in vacuo. The resulting residue was dissolved in methylene chloride and treated
with IN HC1 in water. The desired product precipitated from solution and was collected by
filtration(0.1 lg, 10%). EI-MS m/z 324(M+H) +
Examnle 23
Preparation of N-(2-hvdroxv-4-nitrr>ph e nvn-N l -f?-niu-onh^nvl^ir^,
N-(2-Hydroxy-4-nitrophenyl)-N , -(2-nitro phenyl)urea was prepared from 2-hydroxy
4-nitro aniline (500 mg, 3.24 mmol) and 2-niiro phenyl isocyanate (3.24 mmol) according to
the procedure in General Method B. The product was purified by dilution with methylene
chloride and precipitauon with hexanes. Filtering afforded the title compound(0.44 g. 44%).
EI-MSm/z319(M+H) +
Example 24
Preparation of N-(2-hvdroxv-4-nitrnnh envn-N l -f?-n.ioronhenvnnr Pa
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluorophenyl)urea was prepared from 2-hydroxy
4-nitro aniline (500 mg, 3.24 mmol) and 2-fiuoro phenyl isocyanate (3.24 mmol) according to
the procedure in General Method B. The product was purified by dilution with methylene
chloride and precipitauon with hexanes. Filtering afforded the title compound(().5M u. )
EI-MS m/z 292(M+H) +
Example 25
P reparation of N-(2-hvdroxv-4-niironhenvn-N: i -(2.6-dini](^ronhenvl)iir(M
N-(2-Hydroxy-4-niirophenyl)-N'-(2.6-dilluorophenyl)urea was prepared from 2-
hydroxy 4-nitro aniline (500 mg. 3.24 mmol) and 2.6-difluoro phenyl .socyanaie(3.24 mmol.
according to the procedure in General Method B. The product was purified by dilution with
methylene chloride and precipitation with hexanes. Filtering afforded the title com poundfO.y I
g. 91%). EI-MS m/z 308CM-H) "
Example 26
Preparation of N-(?-hvdr()xv-4-nii ronhenvh-N , -(2-eihoxvnhpnvnnr.\i
N-(2-Hydroxy-4-nitrophenyl)-N , -(2-cihoxyphenyl)urca was prepared from 2-hydmx\
4-nitro aniline (500 mg. 3.24 mmol) and 2-cthoxy phenyl isocyanate (3.24 mmol) according
to the procedure in General Method B. The product was purified by dilution with methylene
chloride and precipitation with hexanes. Filtering afforded the title compound(()84 g. 81% >.
EI-MS m/z 3 1 8(M+H) +
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Example 27
Preparation of N-(2-hvdroxv-4-nitrophenvl)-N'-(2-ethylphenvl)urca
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-cthylphcnyl)urca was prepared from 2-hydroxy 4-
nitro aniline (5(X) mg, 3.24 mmol) and 2-eihyl phenyl isocyanatc (3.24 mmol) according to the
5 procedure in General Method B. The product was purified by dilution with methylene chloride
and precipitation with hexanes. Filtering afforded the title compound(0.44 g, 43%). EI-MS ml v.
302(M+H) +
Example 28
10 Preparation of N-(2-hvdroxv-4-nitro phenvI)-N'-f2-trinuoromethoxvphcnvl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trinuoromethyloxyphenyl)urea was prepared from
2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromeihoxy phenyl isocyanate
(3.24 mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title
1 5 compound(0.69 g. 60%). EI-MS m/z 358(M+H) +
Example 29
Synthesis of N-(2-hvdroxv-4-nitro phenyl) N'-(2-methvlthio phenyl) urea
The urea was prepared from 2-hydroxy 4-nilro aniline (5(X) mg . 3.24 mmol) and 2-
20 methylthio phenyl isocyanaie(3.24 mmol) by general Method B The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title
compoundCO.63 g. 61%). EI-MS m/z 32()(M+H) +
Example 30
25 Synthesis of N-(2-hvdroxv-4-nitro phenyl) N'-(2-chloro 6-methyl phenyl) urea
The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg. 3.24 mmol) and 2-
chloro 6-methyl phenyl isocyanate by general Method B. It was purified by dilution with
methylene chloride and precipitation with hcxanc. Filtering afforded the desired
compound(0.31 g. 29%). EI-MS m/z 322(M+H> +
30
Example 31
Synthesis of N-(2-hvdroxv-4-nitro phenyl) N'-(2- methyl sulfoxvphenvi ) urea
The urea was synthesized by treatment of N-( 2-hydro.\\ 4-nitro phenyl) N'-(2-mcthyl
thio phenyl) urea(cxample 28. 100 mg) with sodium pcriodatei 100 mm in i-butanol/waier lor
35 12 hours at 23 °C. The product precipitated from the reaction mixiui e(30 mg. 29% ). EI-MS
m/z336(M+H) +
Example 32
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Synthesis of N-(2-hvdroxv 4-trifl uoromct.hvl nhcnvh N'-(2-hromo phenyl) mtca
The urea was prepared from 2-hydroxy 4-trifluoromethyl anilinetexamplc 7a. 0. 17 |g.
1 mmol) and 2-bromo phenyl isocyanated mmol) by general Method B. It was purified by
dilution with methylene chloride and precipitation with hexanc. Filtering afforded the desired
compound(0.25 g, 54%). EI-MS m/z 375(M+H) +
Examnle 33
Synthesis of N-(2-hvdroxv 4-carho m cthoxv phcnvh N'-P-hromo phpnvh y rgj
The urea was prepared from 2-hydroxy 4-carhomethoxy aniline((). 167 g. 1 mmol) and
2-bromo phenyl isocyanated mmol) by general Method B. It was purified by dilution with
methylene chloride and precipitation with hexanc. Filtering afforded the desired
compound(0.12 g. 33%). EI-MS m/z 363(M-H)-
Examnle 34
Synthesis Of N-(2-hvdroxv 4-trinnnmmethvl nhenvl ) N , -f2-phffnvl phenyl) urea
The urea was prepared from 2-hydroxy 4-trifluoromethyl anilinetexample 7a, 0.171 g,
1 mmol)) and 2-phenyl phenyl isocyanate by general Method B. It was purified by dilution
with methylene chloride and precipitation with hexanc. Filtering afforded the desired
compound(0.24 g, 64%). EI-MS m/z 373(M+H) +
Examnle 3S
Synthesis of N-(2-hvdroxv 4-carhom cthoxv phenyl) N'-P-phcnvl nhenvh urn?
The urea was prepared from 2-hydroxy 4-carbomclhoxy anilinc((). 1 67 g. 1 mmol) and
2-phenyl phenyl isocyanated mmol) by general Method B h was purified by dilution with
methylene chloride and precipitation with hexanc. Filtering afforded the desired
compound^). 185 g. 509, ). EI-MS m/z 363(M-H) "
Examnle 3(S
Synthesis of N-(2- hydroxv 4-nii r o phen yl) N'-(2. 3-dichlom nhrnvh it.m The urea was
prepared from 2-hydroxy 4-nuro anilinc(30S mg. 2 mmol) and 2.3-dichloro phenyl
isocyanate(2 mmol) by general Method B. Ii was purified by dilution with methylene chloride
and precipitation with hexanc. Filtering afforded the title compoundf().5 g. 7.V/7 > EI-MS m//
342(M+H) +
Example 37
Synthesis of N-(2-hvdroxv 4-nitro phenyl) N'-(2.4-dichloro phenyl
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The urea was prepared from 2-hydroxy 4-nilro aniline(3()8 mg. 2 mmol) and 2,4-
diehloro phenyl isocyanate(2 mmol) hy general Method B. h was purified by dilution with
methylene chloride and precipitation wilh hexanc. Filtering afforded the title compound(0.26
g. 38 ). EI-MS m/z 342 fM+H) +
5
Example 38
Synthesis of N-(2-hydroxy-4-nitro phenyl) N'-(2-chloro phenyl) urea
The urea was prepared from 4-nitro 2-hydroxy aniline(3()8 mg, 2 mmol) and 2-chloro
phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene
10 chloride and precipitation with hexane. Filtering afforded the title compound(0.29 g. 47%).
EI-MS m/z 308(M+H) +
Example 39
Synthesis of N-(2-hvdroxy-4-nitrophenvl) N'-(2.4-dibromo phenyl) urea
15 The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg. 2 mmol) and 2,4-
dibromo phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with
methylene chloride and precipitation wilh hexane. Filtering afforded the title compound(0.34
g. 39<7r). EI-MS m/z 43<)(M+H) +
20 Example 40
Synthesis of N-(2-hvdroxynapthvl) N'-(2-hromo phenyl) urea
The urea was prepared from 1-amino 2-hydroxy napthalenc( 195 mg. 1 mmol) and 2-
bromo phenyl isocyanatc( 1 mmol) by general Method B. It was purified by dilution with
methylene chloride and precipitation with hexanc Filtering afforded the title compoundfO.030
25 g. 87,}. EI-MS m/z 357(M+H) +
Example 4 1
Synthesis of N-(2-hvdroxy-4-nitrophcnyl )-N'-(2,3-mcthylcnedioxyphcnyl)urea
30 alPrcparation of 2.3-mcihylcncdioxyphcnylcarboxylic acid
A solution of 1 .3-nenzodioxole (3.09 g. 32 mmol) in dry ether (50 mL) was treated
dropwisc at -10T with 2.5 M n-butyllilhium (15 mL. 35 mmol) in hexane. When the addition
was complete, the mixture was stirred under reflux lor one hour. After cooling to room
temperature, il was added to crushed solid carbon dioxide, and after 24 hours, the residue was
35 treated with 10 c /< aq. NaHCOi and ether. The alkali layer was separated, washed with ether,
then acidified with cold concentrated HC1. and extracted with chloroform. The combined
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organic layers were dried over MgS0 4 . filtered and concentrated under reduced pressure ( 1 i
g. 20 %). EI-MS m/z 167 (M+H)"
(^Preparation of N-(2-hydroxy-4-nitrophenyl)-N , -(2,3-methylencdioxyphenyl)urea
To a solution of the 2,3-methylenedioxyphenylcarbojtylic acid in toluene, triethylamme
(0.27 mL. 1.95 mmol) and diphenylphosphoryl azide (DPPA) (0.32 mL. 1.5 mmol) were
added. The reaction mixture was stirred at 60°C for 2 hours, then 2-amino-5-nitrophenol (250
mg, 1 .5 mmol) was added. The reaction mixture was stirred at 100°C lor 1 8 hours. After the
reaction mixture was cooled to room temperature, it was partitioned between 5 % citric acid and
ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times
with ethyl acetate. The organic extracts were combined, dried over MgS0 4 , filtered and
concentrated under reduced pressure. Chromatography of the resulung solid on silica gel
(hexane : ethyl acetate; 5: 1 ) gave product (200 mg, 42 %). EI-MS m/z 3 1 8 (M+H)*
Example 4?
Synthesis of N-(2-hYdrPXV 4-nitro Phenyl) N-r2-m P .thnvv V c hloro nhenvh nrea
The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2-chlor
3-methoxy phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with
methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.48
g, 63<7r). EI-MS m/z 338(M+H) +
Example 43
Synthesis of N-(2-hvdroxv 4-niirn ph e nyl) N'-P-methvl phrnvh nr rP
The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg. 2 mmol) and 2-methyl
phenyl isocyanalc(2 mmol) by general Method B. It was purified by dilution with methylene
chloride and precipitation with hexane Filtering afforded the title compound(0.38 g. 539? )
EI-MS ml/ 2XX( M+H) +
Examnle 44
Synthesis of N(his (2-hvdroxv 4-niiro p henyl) N'-rrtianisdinei dmr^
The urea was prepared from 2-hydroxy 4-nitro aniline(6 1 6 mg. 4 mmol) and
dianidisdinc diisocyanatc(2 mmol) by general Method B(cxccpl 2 equiv. oi 4-nitro 2-hydroxy
aniline was used instead of lequiv). The product was purified by dilution with methylene
chloride and precipitation with hexane. Filtering afforded the title eompound( 0.08 g. 6V7 ).EI
MS m/z 6()5(M+H) +
Example 45
Synthesis of 4-mcthvlcne bis(N-(2-chloro nhenvl) N'-f2-hvrtniw 4-nitro
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The urea was prepared from 2-hydroxy 4-nitro aniline(616 mg. 4 mmol) and 4-
methylcnc bis(N-(2-chloro phenyl) diisocyanate(2 mmol) by general Method B(except 2 cquiv
of 4-nitro 2-hydroxy aniline was used instead of lequiv.). The product was purified by
dilution with methylene chloride and precipitation with hexane. Filtering afforded the title
5 compound(O.K) g, 8%).
EI-MS m/z 627(M+H) +
Example 46
Synthesis of N-f2-hvdroxv 4-(benzylamino)carbonvl phenvll-N'-(2-hromophenvl)urea
10 a)Synthesis of N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 3-hydroxy 4-amino benzoic acid (3.69 g, 24 mmol) and 2-
bromo phenyl isocyanate(24 mmol) by general Method B. It was purified by dilution of the
DMF solution with methylene chloride and precipitation with hexane(4.0 g, 48%). EI-MS m/z
35KM+H) +
1 5 b)Preparauon of N-[4-(benzylamino)carbonyl-2-hydroxyphenyl]-N'-(2-bromophenyl)urea
To a solution of the N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea
(200 mg, 0.58 mmol) in DMF ( 1 5 mL), EDC ( 1 2 1 .9 mg, 0.58 mmol), HOBT ( 1 56.6 mg.
1 1.6 mmol) were added . The reaction mixture was stirred at room temperature for 16 hours.
Then the benzyl amine (123 mg, 1 1.6 mmol) was added. The reaction mixture was stirred at
20 same temperature for 24 hours. Then the reaction mixture was partitioned between water and
ethyl acetate. The organic layer was separated and the aqueous layer was extracted three times
with ethyl acetate. The organic extracts were combined, dried over MgS0 4 . filtered and
concentrated under reduced pressure. Chromatography of the resulting solid on silica gel
(hexane : ethyl acetate; 1:1) gave benzylamino product (500 mg. 65 %). EI-MS m/z 44 1
25 (M+HV
Example 47
Synthesis of N-(2-hvdroxv 4-nitro phenyl) N'-(2-phenoxv phenyl) urea The urea was
synthesized by the treatment of 2-phenoxyphenyl carboxylic acid(2 mmol.) with diphenyl
30 phosphory! azide(0.475 mL) and triethyl amine(. 14 mL) in DMF at 80 °C alter 24 hours the 2-
amino 5-nitro phenol (1 equiv.) was added. The reaction was heated for 24 hours at 80°C. The
reaction product was oiled out with hexane. The residue was dissolved in methanol and the
solid was precipitated out with water. ( 180 mg. 24 c 7r ) EI-MS m/z 364(M-H)
35
Example 48
Synthesis of N-(2-hvdroxv-4-fluoro phenyl) N'-(2-hromo phenyl) urea
a)Synthesis of 2-hydroxy 4-fluoro aniline
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3-fluoro 6-nitro phenol (2 g. 1 1 mmol) was Ireatcd with 10%Pd/C< I g) al 23 °C. The
reaction mixture was Hushed with hydrogen gas and the reaction was allowed to stir 12 h
before it was filtered through eclitc. The filtrate was concentrated in vacuo to afford the title
compound (1.4 g, 77%). EI-MS m/z 169(M+H) +
5 b)Synthesis of N-(2-hydroxy-4-fluoro phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg. 2 mmol) and 2-
bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene
chloride and precipitation with hexane( 173 mg. 26%). EI-MS m/z 325 (M+H) +
K) Example 49
Synthesis of N-( 2-hydroxv 3.4-difluoro phenyl) N'-(2-hromo phenyl) urea
a) Synthesis of 2-hydroxy 3,4-difluoro aniline
2,3 difluoro 6-nitro phenol (2 g, 1 1 mmol) was treated with 10%Pd/C(l g) at 23 "C
The reaction mixture was flushed with hydrogen gas and the reaction was allowed to stir 12 h
1 5 before it was filtered through celite. The filtrate was concentrated in vacuo to afforded the title
compound (1.6 g. 97%). EI-MS m/z 146(M+H) +
b) Synthesis of N-(2-hydroxy 3,4-difluoro phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 2-hydroxy 3.4-difluoro aniline(0.290 g, 2 mmol) and 2-
bromo phenyl isocyanate(0.4 g) by general Method B. It was purified by dilution with
20 methylene chloride and precipitation with hcxane(0.254 g. 37%). EI-MS m/z 343(M+H) +
Example 50
Synthesis of N-(2-hvdroxv 3-napthvn N'-(2-bromo nhenvl) urea
The urea was prepared from 3-amino 2-hydroxy napthalenc(0.320 g. 2 mmol) and 2-
25 bromo phenyl isocyanate(40 g) by general Method B. It was purified by dilution of the with
methylene chloride and precipitation with hcxane(0.339. 47%). EI-MS m/z 357(M+H) +
Example 5 1
Synthesis of N-(2-hvdroxy 4-phcnvl phenyl) N'-(2-hrom.o phenyl) urea
30 a)Synthesis of 2-nitro 5-phenyl phenol
A solution of 3-phenyl phenol(2 g. 1 1 mmol ) in acetic acid was treated with
concentrated nunc acid drop-wise until all starting material was consumed. The solution was
partitioned between water and methylene chloride. The organic phase was separated and the
aqueous phase was extracted once more with methylene chloride. The combined organic
35 phases were dried over sodium sulfate, filtered and concentrated //; vacuo. The residue was
purified by silica gel chromaiography(ethyl acctatc/hexanes) to afford desired ( 1.2 g. 50%). 'H
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NMR (CDCh): 6 10.65(s. 1H), 8.18 (d. 1 H. J = 10.0 Hz). 7.65 (d. 2H. J = 6.0 Hz). 7 4V
(m. 3H). 7.34 (s. 1H), 7.10 (d, 1H, J=10.0Hz)
b) Synthesis oi 2-amino 5-phenyl phenol
A solution of 2-nitro 5-phenyl phenol(1.2 g, 5.5 mmol) in methanol was treated with
10% Pd/C(1.2g). The reaction mixture was Hushed with hydrogen and allowed to stir
overnight. The reaction mixture was filtered through celite and the filtrate was concentrated /■
vacuo to afford desired (1.01 g, 98%).EI-MS m/z 186(M+H) +
c) Synthesis of N-(2-hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea
The urea was prepared from 2-hydroxy 4-phenyl aniline(0. 185 g. 1 mmol) and 2-
bromo phenyl isocyanate(0. 1 98 g) by general Method B. It was purified by dilution of the
DMF solution with methylene chloride and precipitation with hexane(215 mg. 56%).EI-MS
m/z 383(M+H) +
Example 52
15 Synthesis Of N-(-2-hvdroxv 4-methvl ph enyl) N'-f?-hromo phenyl) ..ma
The urea was prepared from 2-hydroxy 4-melhyl aniline(.274g. 2 mmol) and 2-bromo
phenyl isocyanate(0.40 g, 2 mmol) by general Method B. It was purified by dilution of the
DMF solution with methylene chloride and precipitation with hexane(249 mg, 39%). EI-MS
m/z319(M-H)"
20
Examnle 53
Syndesis of N(2-hvdroxv 4-nitro phenyl) N , -f ?.-nhcnvlamino nhenvh urea
The urea was synthesized by the treatment of 2-tertbutyldimcthylsilyloxy 4-niiro phen \ 1
isocyanatefexample 9a. 0.4 19g, 1.5 equiv.) with 2-anilino aniline(0 .1X4 g. 1 cquiv .» in THI
25 overnight at 40 °C. The desired product precipitated out of the reaction mixmrcf30 nig. X<7, i
EI-MS m/z 365(M+H) +
Example 54
Synthesis of N-(2-hvd roxv 3-carhoxvlate phenyl) N'-f2-bromo phenyl > nrr;i
The urea was prepared from 2-hydroxy 3-amino benzoic acid(3(K) mg. 2 mmol) and 2-
bromo phenyl isocyanate by general Method B. It was purified b\ dilution of the DMF
solution with methylene chloride and precipitation with hexane(.2K7 n. ). EI-MS ml/
351(M+H) +
35
Example 55
Synthesis of N(2-sulfhvdrvl 4-hr omo phenyl) N"-(2-hrnmo phenyl) urn:,
a)Synthesi.x of 2-amino 6-bromo thiazole
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4-Bromo aniline(4.3 g, 25 mmol, 1 eqmv.) and ammonium thiocyanatc(5.7 g. 3equiv.)
was dissolved in acetic acid and treated with bromine(4 g, lequiv.) at room temperature. Alter
complete disappearance of starting material the reaction mixture was poured into water and the
solid was collected. The solid was used in the next step without any purification(3.6 g. 46% ).
EI-MS m/z 229(M+H) +
b) Synthesis of bis (3-bromo 6-amino phenyl) disulfide
The 2-amino 6-bromo thiazole hydrobromide (500 mg, 1.6 mmol) in watcr(5mL) was
treated with KOH (2.5 g) was heated at reflux for 8 h at reflux. The reaction mixture was then
acidified to ph 4 with acetic acid and extracted with methylene chloride. The methylene
chloride mixture was concentrated in vacuo. The residue was dissolved in DMSO and treated
with 1 2 . After stirring overnight at room temperature the reaction mixture was partitioned
between methylene chloride and saturated sodium bicarbonate. The methylene chloride layer
was dried with magnesium sulfate and concentrated in vacuo. The resulting solid was purified
by flash chromatography(ethyl acetate/hexane) to afford the title compound (230 mg. 34%).
EI-MS m/z 405(M+H) +
c) Synthesis of N(2-sulfhydryl 4-bromo phenyl) N'-(2-bromo phenyl) urea
A solution of (3-bromo 6-amino phenyl) disulfide(201 mg, .5 mmol) in DMF was
treated with 2-bromo phenyl isocyanate( 1 mmol) at 80 °C overnight. The reaction mixture
was diluted with methylene chloride and a solid was precipitated out with hcxancs. The
solution was dissolved in MeOH and treated with NaBH 4 . After gas evolution ceased the
reaction mixture was carefully acidified with IN HQ and the resulting solid was l'iltered(52
mg. 13%). EI-MS m/z 399 (M-H) '
Example 56
Synthesis of N-f2-hvdroxv 4-nitro nhenvl) N'-(2-iodo phenyl) urea
The urea was synthesized by the treatment ol" 2-iodo benzoic acid(5 s:. 20 mmol) with
diphenyl phosphoryl azidc( 1 equiv.) and triethyl amine ( 1 equiv.) in DMF at 80 °C alter gas
evolution ceased the 5-nitro 2-amino phenol (3 g. 1 equiv.) was added. The reaction was
heated overnight at 80°C. The reaction mixture was purified by filtering through a plug ol
silica with methylene chloride. The desired product was then precipitated out with hcxanc.
Filtering afforded the desired compound(l.()8 g. 13%). EI-MS m/z 398(M-H)
Example 57
Synthesis of N-(2-hvdroxv 4-nitro nhenvl) N'-(2-hromo phenyl) thiourea
The thiourea was synthesized by treatment of the 2-/m-butyldimcthylsilyloxv 4-nitro
phenyl thioisocyanate(see example 9a . 3.73 mmol) with 2-bromo aniline in toluene at 88°C
over 36 h. The solution was concentrated and the residue was purified bv flash
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chromaiography(EtOAc/Hexanes). The fraction slightly lower rl ihan starting matcnal
contained the desired compound. This fraction was concentrated and then treated with trie thy J
amine hydrofluoride in acetonilrile for 15 minutes at 23 °C. The reaction mixture was then
concentrated in vacuo and the residue was purified by Hash chromatography(cihy)
5 actate/hexanes) to give N-(2-hydroxy 4-nitro phenyl) N'-(2-bromo phenyl) ihiourea ( "52 mg.
4%) . EI-MS m/z 369(M+H) +
Example 5X
Synthesis of N-(2-nhenvlsulfamido) 4-cva nonhenvl N'.(2-hmmo phenyl) urea
1 0 a)Synthesis of 3-(phenylsulfamido) benzoniirile
The of 3-(phenylsulfamido) benzonitriJe was synthesized from the 3-cyano aniline
(23.9 g, .2 mol) by Method C. It was purified by recrystalization from EtOH( 15.8 g.
31%).lH NMR (CDC1 3 ): 6 7.95(s, 1H), 7.84 (d, 2H, J = 8.0 Hz), 7.59 (l. IH. J = 8.0 Hz).
7.45 (m, 2H), 7.35 (m, 4H).
15 b)Synthesis of 3-(phenylsulfamido) 4-nitro benzoniirile
The 3-(phenylsulfamido) benzonitrile( 10 g, 39 mmol) was dissolved in acetic
anhydride and treated with concentrated nitnc acid dropwise at room temperature until all the
starting material had been consumed. The reaction mixture was then quenched by carefully
pouring it into sodium bicarbonate and left to sit until all gas evolution had subsided. It was
20 then partitioned between methylene chlonde and water. The organic layer was dried over
sodium sulfate and filtered. The reaction mixture was concentrated in vac uo, absorbed onto
silica gel and purified by column chromatography! methylene chloridc/hcxano to afford the title
compound (1.7g, 15%). EI-MS m/z 302(M+H) +
c)Synthesis of 3-(phenvLsulfamido) 4-ammo benzoniirile
25 The 3-(phenylsulfamido) 4-nitro benzomtnle( 1.5 g. 4.9 mmol) was treated with tin
chloride dihydrate in EtOH at 80 °C for 1 2h. It was ihcn concentrated and Hushed through a
plug of silica gel with 5% methanol/methylene chloride. The filterate was absorbed unto silica
gel and purified by Hash chromaiography(ethyl acctatc/hcxane) to afford the title compound
(0.9 g. 60%). EI-MS m/z 274 (M+H) +
30 d)Synthesis of N-(2-phenylsulfamido) 4-cyanophenyl N'-(2-bromo phenyl > urea
The urea was synthesized from 2-(phcnylsullamido) 4-amino bcn/onitrile(77 mg. 0.2S
mmol) and 2-bromo phenyl isocyanate by general Method C. It was purified by column
chromaiographytelhyl aceiatc/hexanc) lo afford the title compound (30 mg. 22 ( 7, >. EI-MS ml/
469(M-H) "
Example 59
Synthesis of N-(2-(phenvl sulfam ido) phenyl) N'-(2-hromo phenyl) urea
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10
15
20
a) Synthesis of 2-( phenyl sulfamido) aniline
The sulfonamide was synthesized from phenyl sulfonyl chJnndc(0.01 mmol) and o-
phenylenc diaminc( 1 .08 g, 0.0 1 mmol) by general Method C. It was purified by
recrystallization from EtOH( I .() g, 40%).EI-MS m/z 249(M+H) +
b) Synthesis of N-(2-(phenyl sulfamido) phenyl) N'-(2-bromo phenyl) urea
The urea was synthesized 2-(phenyl sulfamido) anilinc( 1 mmol)
and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with
methylene chloride and precipitation wiih hexanc. Filtering afforded the desired
compound(0.234 g, 52%).EI-MS m/z 446(M+H) *
Examnle 60
SvnftgSiS Of N-(2-( srvrvl sulfamido) phen y l} N'-P.-hmmn phenyl)
a) Synthesis of 2-( styryl sulfamido) aniline
The sulfonamide was synthesized from styryl sulfonyl chlonde(0.0l mol) and o-
phenylene diamine(0.01 mol) by general Method C. I. was purified bv rccrystall.zai.on from
EtOH(1.2 g, 60%)EI-MS m/z 199(M+H) + .
b) Synthesis of N-(2-(styryl sulfamido) phenyl) N-(2-bromo phenyl) urea
The urea was synthesized from 2-(styryl sulfamido) anihnc( I mmol) and 2-bromo
phenyl isocyanaied mmol) by general Method B. It was purified by dilution with methylene
chloride and precipitation with hexane. Filtering afforded the desired compound(0.309 g.
65%). EI-MS m/z 472(M+H) +
30
35
Example 61
Synthesis of 2-f(3,4 dwlhoxvphcnvhsnlfonvl amino | p h enyl) \"-t->-hr„mo nhrnvh nrr,
a) Synthesis of 2-[(3.4-dimethoxyphcnyl)sulfonyl amino|phcny) aniline
The sulfonamide was synthesized from 3.4-dimcthoxy phenyl sulfonyl chloride(0 .0 1
mol) and o-phenylenc diamine by general Method C. It was purified by rccrvstallizatmn from
EtOH(0.65 g, 21%). EI-MS m/z 309(M+H) + .
b) Synthesis of 2-|(3.4-dimcthoxyphenyl)sulfonylaminoj phenyl) V-C-bromo phenyl) urea
The urea was synthesized from 2-[(3.4-dimethoxyphenyl jsulionyl amino)phenyl
anilined mmol) and 2-bromo phenyl isocyanate by general Method B It was purified "by
dilution with methylene chloride and precipitation with hexane Filtering afforded the desired
compound(0.062 g. 1 297 l.EI-MS m/z 504(M-H) "
Example 62
Synthesis of N-(2-|(4-acetamidonhenvlKnlt o nvlaminol phenyl) N-(2-hmmo nhenvh urea
a)Synthesi.sof2-|(4-acetamidophenyl)sulfonylamino]phcnyl aniline
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The sulfonamide was synthesized ironi 4-acctamidophcnyl sulfonyl chloridcfO.Ol mol)
and o-phcnylcnc diannne(().()l mol) by general Method C. It was purified by recrystallization
from EtOH( 1.27 g.40<7r)EI-MS m/z 304(M-H) .
b)Synthesis of N-(2-[(4-acetamidophcnylsulfonyl)amino| phenyl) N'-(2-bromo phenyl) urea
5 The urea was synthesized from 2-|(4-acetamidophenyl)sulfonylamino]phenyl aniline( 1
mmol) and 2-bromo phenyl isocyanatc(l ramol) by general Method B. It was purified by
dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired
compounds. 12 g. 24%). EI-MS m/z 501 (M-H)
10 Example 63
Synthesis of N-(2-f2-thiophene sulfamido phenyl) N'-(2-bromo phenyl) urea
a) Synthesis of 2-(2-thiophene sulfamido) aniline
The sulfonamide was synthesized from 2-thiophene sulfonyl chloride(0.01 mol) and o-
15 phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization from
EtOH(0.77 g, 30%). EI-MS m/z 255 (M+H) +
b) Synthesis of N-(2-(2-thiophenc sulfonyl amino phenyl) N'-(2-bromo phenyl) urea
The urea was synthesized from 2-( 2-thiophene sulfonyl amino) anilined mmol) and
2-bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with
20 methylene chloride and precipitation with hexane. Filtering afforded the desired
compound(0.29 g. 64<7 f ). EI-MS m/z450(M-H) '
Example 64
Synthesis of N-(2-(3-tolvl sulfonyl amino nhcnvl) N'-(2-bromo phenyl) urea
25 a)Synthesis of 2-( 3-tolyl sulfonyl amino) aniline
The sulfonamide was synthesized from 3-lolyl sulfonyl chlonde(().()l mol) and o-
phenyicne diaminc(0.01 mol) by general Method C. ll was purified by recrystallization from
ElOH(0.73g. 28'*). EI-MS m/z 263 (M+H) +
b)Synthesis of N-(2-(( 3-tolyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea
30 The urea was synthesized from 2-(3-iolyl sulfonyl amino) anilinef 1 mmol ) and 2-
bromo phenyl isocyanate( 1 mmol) by general Method B. It was purified by dilution with
methylene chloride and precipitation with hcxancs. Ii was rccrysallized two times with
EtOH(25 me. 59; ). EI-MS m/z 45X(M-H) "
35
Example 65
Synthesis of N-(2-(K-quinolinyl sulfonyl amino) phenyl) N'-(2-hromo phenyl) urea
a)Synlhcsis of 2-(8-quinolinyl sulfonyl ammo) aniline
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The sulfanamide was synthesized from 8-quinolinyl sulfonyl ehlondc(0.0] mol) and <
phenylenc diaminc«).()l mol) hy general Method C. It was purified by reerysiaJlization from
EtOH(0.82 g. 279f-).EI-MS m/z 300 (M+H) *
b)Synthesis of N-(2-( (8-quinolinyl) sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea
The urea was synthesized from 2-((8-quinolinyl) sulfonyl amino) anilined mmol) and
2-bromo phenyl isocyanatcd mmol) by general Method B. It was purified by dilution with
methylene chloride and precipitation with hexanc. Filtering afforded the desired
compound(0.23 g. 46^ ). EI-MS m/z 495CM-H) "
Examnle 66
Synthesis of N-(2-( hcnzvl sulfonvl amino) nhan v l) N'-(2-hrnmo nhfmvh nn»a
a) Synthesis of 2-(bcnzyI sulfonyl ammo) aniline
The sulfonamide was synthesized from benzyl sulfonyl chloride(0.01 mol) and o-
phenylene diamine(().OI mol) by general Method C. It was purified by recrystallization from
EtOH(0.87g, 33%). EI-MS m/z 263(M+H)+.
b) Synthesis of N-(2-( benzyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea
the urea was synthesized from 2-( benzyl sullonyl amino) anilined mmol)
and 2-bromo phenyl isocyanate(lmmol) by general Method B. It was purified by dilution
with methylene chloride and precipitation with hexanc. Filtering afforded the desired
compound((). 1 1 g. 23'* > EI-MS m/z 460 (M+H)+
Example 67
Synthesis of N-(2-hvdroxv-4-a/icln nhcnvn-N'-f2-meih»xvphenvnurp.a
a)Synthesis of N-(2-hydroxy-4-aminophcnyl)-N'-(2-methoxyphcnyl )urca
To a solution of N-(2-hydroxy-4-nitro phenyl »-N"-(2-mcthoxyphenyl )urea(l .0 g.
example 15) in methanol, palladium (on activated carbon. ) ( 100 nig) was added. Then the
reaction mixture was hydrogenated under a hydrogen balloon for 18 hours. The solid was
filtered off by celhc and washed three limes by methanol. The filtrate was concentrated under
reduced pressure to give amine compound (O S g. W l 7, ). EI-MS m/z 274 ( M+H)*
blSynlhcsis of N-(2-hydroxy-4-azidophcnyl)-N'-(2-methoxyphenyl)urca
The N-(2-hydroxy-4-aminophenyl)-N - -(2-mcthoxyphenyDurea (300 mg. 1.17 mmol)
was added to HC1/H.O (1.17 mL/2.34 mL). cooled to 0°C. Sodium nitrite (80.7 mg. 1.17
mmol) was added to the reaction mixture. The reaction mixture was stirred at ()°C for 30
minutes. The sodium a/idc (76 mg. 1.17 mmol) was added to reaction mixture and it was
warmed to room temperature. The reaction mixture was stirred at room temperature lor 18
hours. Then it was extracted with three limes by ethyl acetate. The organic extracts were
combined, dried over MgS0 4 . filtered and concentrated under reduced pressure and
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chromatography of the resulting solid on silica gel (hexanc : ethyl acetate: 5:1) gave product
( 1 25 mg. 389? ). El-MS m/z 300 (M+H)*
Example 68
5 Preparation ol N-l 2-hvdroxv-5-cvanophenvll-N , -f2-hromophenvH nrcn
a) Prcparation ol 2-amino-4-cyanophenol
To a solution of 2-nitro-4-cyanophenol( lOg, 61mmol) in mclhanol(250mL) was added
\() c 7, Pd/C ( lg>. The mixture was Hushed with argon, then hydrogen was bubbled through the
solution lor 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight.
10 The mixture was filtered through celiie and the celite was washed with methanol. The solvent
was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH : C1 2 )
gave the desired product(8.0 g, 97%). ! H NMR (CD,OD): 6 6.96 (d. 1H), 6.90 (dd. 1H).
6.77 (d, 1H).
b) Preparalion of N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyll urea
15 N-|2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-
4-cyanophenol(268mg, 2.00 mmol) according to the procedure in General Method B. The
product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering.
(540mg.8l<-7r). 'H NMR (CD 3 OD): 8 8.10 (d, 1H), 7.87 (d, 1H). 7.43 (d. 1H), 7.20 (t. 1H).
7.09 (d. 1H). 6.86 (l, 1H), 6.77 (d, 1H).
20
Example 69
Prcnaration of N-l 2-hvdroxv-3-fluorophenvll-N'-12-bromophenvl 1 urea
a)Prcparation of 2-amino-3-fluorophenol
To a solution of 2-niiro-3-fluorophenol( lg. 6.4mmol) in mcthanol(250mL) was added
25 10';; Pd/C ( lg). The mixture was flushed with argon, then hydrogen was bubbled through the
solution for 10 nun. and a hydrogen atmosphere was maintained at balloon pressure overnight.
The mixture was filtered tnrough celite and the celite was washed with methanol. The solvent
was evaporated and chromatography of the resulting solid on silica gel (5'7rMeOH/ CH:C] : )
gave the desired product(650 mg, 80.2 L 7< ). 'H NMR (CD^OD): 5 6.41-6. 17 (m. 3H).
30 b)Prcparation of N-|2-hvdroxy-3-fluorophcnyl]-N'-[2-.bromophenyl| urea
N-|2-Hydroxy-3-iluorophenyl|-N'-|2-nromo phenyl] urea was prepared from 2-
amino-3-fluorophenol (254mg. 2.00 mmol) according to the procedure in General Method B
The product was purified by precipitation from methylene chloride/ hexanc( 1/20) and filtering.
(500 mg. 11'/, ). 'H NMR (CD.OD): 8 8.05 (d. 1H). 7.50 (d. 1H). 7.26 (l. 1H). 7.18 (d.
35 1H). 6.92 (i. IH). 6.86-6.68 (m, 2H).
Example 70
Preparation of N-2-1 1 -hvdroxvfluorenel-N"-(2-hromophenvl I urea
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a) Preparation of 2-amino- 1 -hydroxyfluorene
To a solution of l-hydroxy-2-nitronuorene(25() mg, 1.23mmol) in methanol(250mL)
was added 10% Pd/C (lg). The mixture was Hushed with argon, then hydrogen was bubbled
through the solution for 10 mm. and a hydrogen atmosphere was maintained at balloon
5 pressure overnight. The mixture was filtered through celite and the cclitc was washed with
methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel
(5%MeOH/ CH 2 C1 2 ) gave the desired product(l71 mg. 81.2 9r). 'H NMR (CD^OD): 6 7.60
(d. 1H), 7.47 (d. 1H), 7.28 (t. 1H), 7.18 (m, 2H), 6.82 (d. 1H), 3.76 (s. 2H).
b) Preparation of N-2-[ l-hydroxyfluorene]-N'-|2-bromophenyl] urea
10 N-2-[ l-hydroxyfiuorene]-N'-[2-bromo phenyl] urea was prepared from 2- amino- 1-
hydroxyfiuorene (170mg, 0.86 mmol) according to the procedure in General Method B. The
product was purified by chromatography of the resulting solid on silica gel (30%EtOAc/
Hexane) to give the desired product (300mg, 84.5%). 'H NMR (CD,C1): 6 8.04 (d, 1H),
7.66 (d, 1H), 7.49 (t. 2H), 7.35-7.20 (m. 4H). 7.09 (d. 1H). 6.90 (t. 1H).
15
Example 71
Preparation of N-3-[2-hvdroxv-9.10-anthra quinonvll-N l -r2-hromonhpnvll nre.a
N-3-[2-Hydroxy-9.10-anthraquinonylJ-N , -[2-bromophenyl| urea was prepared from
2-hydroxy-3-aminoanthraquinone(480mg, 2.(X) mmol) according to the procedure in General
20 Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20)
and filtering. (610mg, 70%). *H NMR (CD,OD): 6 8.93 (s.lH). 8.12 (m. 2H). 8.02 (d.
IH). 7.77 (m. 2H). 7.61 (d. 1H), 7.52 (s, 1H), 7.38 (t. 1H). 7.05 (l. 1H).
Examnle 72
25 Preparation of N-f2-hvdroxv-3-flu oro-5-hromonhcnvll-N"-[2-hr»mophcnvl I urea
a) Preparation of 2-amino-6-fluoro-4-bromophcnol
A mixture of 4-bromo-2-fluoro 6-nitrophcnol( I g, 4.2mmol) and tin (II) chloride (4 7X
g. 21.2mmol) in ethanol(5()mL) was heated at 8()°C under argon. After 2 hours, the startint:
material had disappeared and the solution was allowed to cool down and men poured into ice
30 The pH was made slightly basic (pH7-8). by addition of solid NaOH. before being extracted
with ethyl acetate. The organic phase was washed with bnnc. dried over MgSO., and filtered
The solvent was evaporated and chromatography of the resulting solid on silica gel (4'7rMeOH/
CH 2 C1 2 ) gave the desired products 10 mg. 82 <7, ). l H NMR (CD^OD): 6 6.5 1 -6.40 < m. 2H)
b) Preparation of N-[2-hydroxY-3-fluoro-5-bromophcnyl]-N'-[2-bromophenylJ urea
35 N-[2-hydroxy-3-fluoro-5-bromophcnyI]-N'-[2-bromophenyl| urea was prepared from
2-amino-6-fluoro-4-bromophenol (254mg, 2.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/ hexanc( 1/20)
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and tillering. LSOO mg, 77%). ! H NMR (CD.OD): S 7.98 (s, 1H). 7.91 (d, 1H), 7.60 (d.
1H). 7.33 (I, 1H). 7.00 (t, 1H). 6.94 (d. 1H>.
Example 73
5 Preparation of N-f2-hydroxy-3-chlorophenyll-N'-l2-hromophenvll nrt^
a)Preparation of 2-amino-3-chlorophenol
A mixture of 3-chloro-2-nitrophcnol(250 mg, I.4mmol) and tin (II) chloride (1.2 g.
5.3mmol) in elhanol(50mL) was heated at 80°C under argon. Alter 2 hours, the starung
material has disappeared and the solution was allowed to cool down and then poured into ice
10 The pH was made slightly basic (pH7-8). by addition of solid NaOH. before being extracted
with ethyl acetate. The organic phase was washed with bnne. dried over MgS0 4 and filtered
The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/
CH 2 C1 2 ) gave the desired product(l43 mg, 69 %). 'h NMR (CD,OD): 6 6.75 (t.lH). 6.70 (d.
1H), 6.65 (d, IH).
15 b)Preparation of N-[2-hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea
N-[2-hydroxy-3-chlorophenyl]-/V'-[2-bromophenyll urea was prepared from 2-amino-
3-chlorophenol (143mg, 1.00 mmol) according to the procedure in General Method B. The
product was purified by chromatography of the resulting solid on silica gel (30%EtOAc/
Hexane) to give the desired product( 195mg. 57%). 'h NMR (CD^.OD): 6 7.81 (d, 1H). 7 68
20 (d. 1H). 7.47 (d, 1H). 7.20 (l, IH). 6.90 (m. 2H), 6.70 (I. IH)
Example 74
Preparation of N-[2-hydroxy-3-trinuoromcthylphcnyl|-N'-l2-bromophenvll urea
a) Preparation of 2-niiro-6-trifluoromcihylphenol
25 2-trifluoromcthylphenol (3.0()g. 18.5mmol) was dissolved in methylene
chlondc(40mL) followed by the addition ol sodium nitrate (1.73g. 20.4mmol). The addition
of sulfuric acid (23 mL/ 3M) was then made, followed by addition ol a catalytic amount ol
sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was
diluted with methylene chloride and extracted with water The organic lavcr was dried over
30 MgS0 4 and filtered. The solvent was ev aporated and chromatography ol the resulting solid on
silica gel (4%McOH/ CH^Cb) gave the desired product(1.84 g. 47 <?,). 'h NMR
(CD^COCDO: 8 8.35 (d.lH). 7.95 (d. IH). 7.13 (i. IH).
b) Preparation of 2-amino-6- irifluoromeihylphenol
A mixture of 6-trinuoromethyl-2-nitrophcnol( 1 .84 g. S.67mmol ) and tin (II ) chloride
35 (6.0 g. 26.2 mmol) in cthanol(15()mL) was heated at 80°C under argon. After 2 hours, the
starting material has disappeared and the solution was allowed 10 cool down and then poured
into ice The pH was made slightly basic (pH7-8). by addition ol solid NaOH. before being
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extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSCX, and
filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel
(4%MeOH/ CH 3 C1 2 ) gave the desired producK 1 .35 g. 88 % ). 'h NMR (CD.OD): 8 6.93 (d.
1H), 6.82 (t, 1H). 6.78 (d, 1H).
^Preparation of N-[2-hydroxy-3- trifiuoromethylphenyI]-N'-[2-bromophenyl] urea
N-[2-hydroxy-3-trinuoromethylphenyll-N , -[2-bromophcnyl) urea was prepared from
2-amino-6-trifiuoromethylphenol <280mg. 1.60 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20)
and filtering. (39(>mg, 65%). 'h NMR (CD,OD): 8 7.99 (d. IH). 7.60 (d, 1H). 7.58 (d,
1H). 7.34 (t, 1H). 7.30 (d. IH), 7.00 (t, IH). 6.96 (d. 1H).
Examnlp 15
Preparation of N-B.4 dinhfinv1-%hvdroxvphenvll -N'42-hrnmonhenvll nrpa
N-[3,4 diphenyl-2-hydroxyphenyll-N'-|2-bromophenyl| urea was prepared from 2-
amino-5,6 diphenylphenol (50mg, 0.19 mmol) according to the procedure in General Method
B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and
filtering (61mg. 69%). 'H NMR (CD,OD): 8 7.97 (d. 1H).7.66 (d, IH), 7.58 (d. IH). 7.31
(l, IH), 7.25-7.00 (m, 1 IH), 6.91 (d, IH).
Example 76
Preparation Of N-r2-hvdroxv-3-glvcinpmethvlftsipnrar honvlnhftnvn-N , -f2-hrnmnphenvll tire.;.
N-f2-hydroxy-3-glycincmethylestcrcarbonylphcnyl|-N , -|2-bromophenyl] urea was
prepared from 6-glycinemcthylestcrcarbonyl-2-aminophcnol (50mg. 0.22 mmol). purchased
from the University of New Hampshire, according lo the procedure in General Method B. The
product was purified by precipitation from methylene chloride/ hexaneC 1/20) and filtering
(65mg. 69%). 'H NMR (CD,OD): 8 8.14 (d. IH). 7.96 id. IH). 7 49 (d. IH). 7.24 u. 2H).
6.89 (dd. IH). 6.81 (t. IH). 4 10 (s.2H). 3.74 (s.3H)
Example 77
Preparation of N-[2-hvdroxv-3-L'lvcine carbonvlnhenvl l-N"-l 2-hromonhen\'l I men
N-|2-Hydroxy-3-glycinecarbonylphenyll-N'-|2-bromophcnyl| urea was prepared from
N-[2-hydr(uy-3-gl>xMnemclhylcsicrcarb()nylphcnyl|-N'-[2-brc)mopheny]| urca(50mg. 0.12
mmol) by stirring in a 3/1 ratio of methanol/watcr ( 10 mL) Addition of 1 cquiv. of lithium
hydroxide was added and stirring continued until the starting material had disappeared. (45m<;.
92%). The product was purified by chromatography of the resulting solid on silica gel (9/1/0. 1
CH 2 C1 2 / MeOH/ AcOH) to give the desired producK I95mg. 57%). *H NMR CCD^OD): 8 8.14
(d. IH). 7.92 (d. IH). 7.60 (d. IH). 7.46 (d. IH). 7.34 (i. IH). 7.04 (t. IH). 6.X2 (l. IH).
3.96 (2H).
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Example 78
Preparation of N-r2-hvdroxv-3.5-diehlorophenvll-N'-12-hromophenvll urea
a) Prcparation of 2-amino-4,6-dichlorophenol
5 A mixture ol 4,6-dichloro-2-nitrophenol(l g, 4.8mmol) and tin (II) chloride (3.2 g,
l4.4mmol) in elhanol(5()mL) was heated at 80°C under argon. After 2 hours, the starting
material had disappeared and the solution was allowed to cool down and then poured into ice.
The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being extracted
with ethyl acetate. The organic phase was washed with brine, dried over MgS0 4 and filtered.
10 The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/
CH 2 C1 2 ) gave the desired product(685 mg, 80 %). 'H NMR (CD 3 OD): 6 6.75 (s.lH), 6.61
(s, 1H).
b) Preparation of N-[2-hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyI] urea was prepared from 2-
15 amino-4,6-dichlorophenol (143mg, l.(X) mmol) according to the procedure in General Method
B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and
filtering. (660mg, 88%). *H NMR (CD ? o6): 5 7.96 (s, 1H), 7.89 (d, 1H). 7.60 (d, 1H),
7.35 (l. 1H). 7.00 (t, 1H). 6.95 (dd, 1 H).
20 Example 79
Preparation of N-l2-hvdroxy-3-nitrophenyll-N'-f2-bromophenyll urea
N-|2-HydroxY-3-nitrophcnyl|-N'-I2-bromophcnyl| urea was prepared from 2-hydroxy-3-
nitroanilinc (1.25g. 8. 1 mmol) according to the procedure in General Method B. The product
was purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (2.4g.
25 X4«i5 ). 'H NMR (CD.OD): 5 X.45 (d. 1H). 7.94 (d. 1H). 7.78 (d. 1H). 7.60 (d. 1H). 7.35 (t.
1H). 7.01 (m, 2H).
Example 80
Preparation of N-[2-hvdroxv-4-naphthalenesulfonic acidl-N'-[2-bromophenyll urea
30 N-[2-hydroxv-4-naphlhalcncsulfonic acid|-N'-[2-bromophenyl | urea was prepared
from 1 -amino-2-hydroxv-4-naphthalensullonic acid (0.48g. 2.0 mmol) according to the
procedure in General Method B and the addition of lmL of triethylamine The product was
purified by precipitation from methylene chloride/ hcxane( 1/20) and filtering. (690 mg. 79% )
'H NMR (CDiOD): 5 8.14 is. 1H). 8.04 (d. 1H). 7.98 (m. 2H). 7.61-7.55 (m. 3H). 7.43 (I.
35 1H). 6.98 (I. 1H).
Example 81
Preparation of N-f 2-hvdroxv-5-naphthalencsullonic acidl-N'-f2-bromophcnvll urea
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N-3-|2-hydroxy-5-naphthalensulfonic acid]-N'-[2-bromopheny]] urea was prepared
from 2-amino-3-hydroxy-6-naphthalensulfonic acid (0.48g, 2.0 mmol) according to the
procedure in General Method B and the addition of I mL of triethylamine The product was
purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (715 mg. 82%)
5 'H NMR (CD ? OD): 5 8.09 (s, 1H), 7.96 (d, 1H), 7.65-7.48 (m. 3H). 7.36 (t, 1H), 7.25~<s.
IH). 7.04 (m. 2H).
Example 82
Preparation of N-[2-hvdroxv-3.4-dichloronhp.n vll-N l -r2-hmmonhenvll nn»a
1 0 a)Preparation of 2-nitro-5.6 dichlorophenol
2.3-dichlorophenol C3.26g, 20mmol) was dissolved in methylene chloride(40mL)
followed by the addition of sodium nitrate (1.88g, 22mmol). The addition of sulfuric acid
(20mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The
mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene
1 5 chloride and extracted with water. The organic layer was dried over MgS0 4 and filtered. The
solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/
CH 2 C1 2 ) gave the desired product(1.8 g. 44 %). *H NMR (CD3COCD?):
5 8.04 (d.lH). 7.15 (d. 1H).
b) Preparation of 2-amino-5.6 dichlorophenol
20 A mixture of 5.6-dichloro-2-nilrophenol( 1 .8 g. 8.7mmol) and tin (II) chloride (5.8 g.
26. 1 mmol) in eihanol(50mL) was heated at 80°C under argon. After 2 hours, the starling
material had disappeared and the solution was allowed to cool down and then poured into ice
The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being extracted
with ethyl acetate. The organic phase was washed with brine, dried over MgSCX, and filtered
25 The solvent was evaporated and chromatography of the resulting solid on silica gel (49< MeOH/
CH 2 C1 2 ) gave the desired producK 1 .4 mg, 90 %). 'H NMR (CD,OD): 5 6.7 1 (d. 1H). 6.45
(d. IH).
c) Preparation of N-I2-hydroxy-3.4-dichloropheny]]-N'-[2-bromophcnyl] urea
N-|2-Hydroxy-3.4-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-
W) amino-5.6-dichlorophenol (35()mg. 2.00 mmol) according to the procedure in General Method
B. The product was purified by precipitation from methylene chloride/ hexane(l/20) and
filtering. (67()mg. 897, ). H NMR (CD,OD): 5 7.90 (d. I H). 7.85 (d. 1H). 7.59 (d. 1H).
7.31 (t. IH). 6.99 (i. IH). 6.96 (d. (IH).
35
Example 83
Preparation of N42-hvdroxv-3-c vanophenvll-N'42-hrnmoph^nvll yrgj j
a)Preparation of 2-nitro-6-cyanophenol
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2- cyanophenol (2.38g. 2()mmol) was dissolved in methylene chloride(40mL) followed
by the addition of sodium nitrate (1.88g, 22mmol). The addition of sulfuric acid (20mL/ 3M)
was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was
allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and
5 extracted with water. The organic layer was dried over MgS0 4 and filtered. The solvent was
evaporated and chromatography of the resulting solid on silica gel (4 c 7rMeOH/ CH 2 C1 2 ) gave
the desired product(1.4 g. 42 %). *H NMR (CD3COCD,): 5 8.47 (d.lH). 8.15 (d. 1H), 7.30
(t, 1H).
b) Preparation of 2-amino-6-cyanophenol
10 A mixture of 6-cyano-2-nilrophenol(600 mg, l.Ommol) and tin (II) chloride (3.2 g.
14.4mmol) in acetic acid(50mL) was heated at 80°C under argon. After 2 hours, the starting
material has disappeared and the solution was allowed to cool down and then poured into ice.
The pH was made slighdy basic (pH7-8), by addition of solid NaOH. before being extracted
with ethyl acetate. The organic phase was washed with brine, dried over MgS0 4 and filtered.
1 5 The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/
CH 2 C1 2 ) gave the desired product(365 mg, 75 %). l H NMR (CDiOD): 8 6.92 (d, 1H). 6.85-
6.69 (m,2H).
c) Preparation of N-[2-hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea
N-|2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-
20 6-cyanophenol (134mg, 1.00 mmol) according to the procedure in General Method B. The
product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering.
(26()mg. 78% ). 'H NMR (CD,OD): 5 7.98 (d. 1H). 7.74 (d. 1H). 7.57 (d. 1H). 7.30 (t.
IHj. 7.22 (d. 1H). 6.98 (i. 1H), 6.94 (l, (1H).
25 Example 84
Preparation of N-l2-hvdroxv-4-cvanophenvn-N'-f2-hrpmophenvll urea
a) Preparation of 2-nitro-5-cyanophenol
3- cyanophenol (2.38g. 20mmol) was dissolved in methylene chloride(40mL) followed
by the addition of sodium nitrate ( l.88g. 22mmol). The addition of sulfuric acid (20mL/ 3M)
30 was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was
allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and
extracted with water. The organic layer was dried over MgS0 4 and filtered. The solvent was
evaporated and chromatography of the resulting solid on silica gel (47rMeOH/ CH 2 C1 2 ) gave
the desired product(91() mg. 28 9f ). 'h NMR (CD3COCDO: 5 8.30 (d.lH). 7.67 (s.lH).
35 7.49 (d. 1H).
b) Preparauon of 2-amino-5-cyanophenol
A mixture of 5-cyano-2-nitrophenol(250 mg. l.Smmol) and tin (II) chloride (3.2 g.
14.4mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours, the starting
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material has disappeared and the solution was allowed to cool down and then poured into ice.
The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being extracted
with ethyl acetate. The organic phase was washed with brine, dried over MgS0 4 and filtered.
The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/
5 CH 2 C1 2 ) gave the desired product(175 mg, 86 %). 'H NMR (CD,OD): 8 7.00 (d, 1H). 6.8X
(s,!H), 6.69 (d, 1H).
c)Preparation of N-[2-hydroxy-4-cyanophenyl|-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-amino-
5-cyanophenol (170mg, 1.27 mmol) according to the procedure in General Method B. The
10 product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering
(310mg, 14%). 'H NMR (CD ? OD): 6 8.25 (d, 1H). 7.91 (d. IH). 7.59 (d. 1H), 7.33 (t.
1H). 7.17 (d, 1H), 7.07 (s, 1H). 7.01 (t. (1H).
Example 85
15 Preparation of N-f2-hvdroxv-4-cva nonhenvll-N l -l4-mp.thoxvr)henvll urea
N-[2-Hydroxy-4-cyanophenyl]-N'-f4-methoxyphenyl] urea was prepared from 2-
amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B.
The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering.
( 1 1 0mg,86%). 'H NMR (CD-,OD): 8 8.23 (d, 1 H), 7.6 1 -7.5 1 (m. 2H). 7.32 (d, 1 H). 7.20
20 (d. IH), 7.15 (d. 1H), 7.03 (s, 1H).
Example 86
Preparation of NM2-hvdroxv-4-c vam)phenvll-N^I2-phenvlpherivll nrpa N-[2-Hydroxv-4-
cyanophenyl|-N'-[2-phcnylphenyl] urea was prepared from 2-amino-5-cyanophenol (170 mg.
25 1.27 mmol) according to the procedure in General Method B. The product was purified by
precipitation from methylene chloride/ hcxanc( 1/20) and filtering. (15()mg, 85%). 'H NMR
(CD-,OD): 5 8.20 (d. 1H), 7.73 (d. 1H). 7.51-7.20 (m. 8H). 7.13 (d. IH), 7.01 (s. (IH).
Examnle 87
Preparatio n of N'-12-hvdroxv-4-cvanophenvll-N , -l2-methvlnhenvll urea
N-[2-Hydroxy-4-cyanophenyl|-N'-|2-mcthylphenyl| urea was prepared from 2-ammo-
5-cyanophcnol (60mg. 0.45 mmol) according to the procedure in General Method B. The
product was purified by precipitation from methylene chloride/ hexancf 1/20) and filtering.
(9()mg, 159, ). 'H NMR (CD,OD): 8 8.25 (d. IH). 7.59 (d. IH). 7.26-7.00 (m. 5H). 2.30 ».s.
35 3H).
Example 88
Preparation of \-f2-hvdrox v-4-cvanophenvll-N'-f2-trifluoromethvlnhRnvll " r ^ a
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N-[2-Hydroxy-4-cyanophenyl)-N'-[2-irinuoromeihy]phenyl| urea was prepared irum
2-amino-5-cyanophcnol (60mg, 0.45 mmol) according lo the procedure in General Method B.
The product was purified by precipitation from methylene chloride/ hcxaneCl/20) and filtering
(1 lOmg, 16%). 'H NMR (CD ? OD): 8 8.25 (d, 1H), 7.81 (d, 1H). 7.68 (d, 1H). 7 61 (1.
5 1H). 7.32 (l. 1H), 7.15 (dd, 1H), 7.09 (s, (1H).
Examnle 89
Preparation of N-f2-hvdroxv-4-cvanonhfinvll-N l -r^-i rinuoromethvlnhenvll urea
N-[2-hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenylj urea was prepared from
10 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B
The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering
(1 14mg, 79%). 'H NMR (CD 3 OD): 5 8.30 (d, 1H), 7.92 (s, 1H). 7.60 <d, 1H). 7.47 (t. 1H).
7.29 (d, 1H), 7.18 (dd, 1H), 7.06 (s, 1H).
Example 90
Preparation of N-r2-hvdroxv-4-cvanophen vn-N l -f4-trifluoromethvlphenvll urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromethylphenyl] urea was prepared from
2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B
The product was purified by precipitation from methylene chloride/ hexane(l/20) and filtering.
(l()8mg. 757r). 'H NMR (CD,OD): 5 8.31 (d. 1H), 7.68 (d. 2H). 7.59 (d, 2H). 7.20 (dd.
1H). 7.07 (s. 1H).
Example 91
Preparation of N-[2-hvdroxv-3-n-propvlnhenvll-N'-l2-hromnnhenvll ure;i
25 a)Preparation ol 2-nitro-6-n-propylphenol
2-n-propylphenol (5.0()g, 36.8mmol) was dissolved in methylene chlonde(4()mL)
followed by the addition of sodium nitrate (3.43g, 40.5mmol). The addiuon of sulfuric acid
(45mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The
mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene
30 chloride and extracted with water. The organic layer was dried over MgS0 4 and filtered The
solvent was evaporated and chromatography of the resulting solid on silica gel (4 l 7< McOH/
CH : C1 ; ) save the desired product(3.2 mg, 48 %). ! H NMR (CD3COCD,): 8 7.W (d.lH 1.
7.46 dd. 1H). 6.90 (I. 1H). 2.70 (I. 2H). 1.70 (m. 2H). 1.00 (t. 3H).
h)Preparaiion of 2-amino-6-n-propylphenol
35 To a solution of 2-nitro-6-n-propylphenol(2g, 1 1 .Ommol 1 in methanol! lOOmL) was
added \()9c Pd/C (200 mg). The mixture was flushed with argon, then hydrogen was bubbled
through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon
pressure overnight. The mixture was filtered through celite and the cclite was washed with
15
20
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methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel
(5%MeOH/ CH 2 C1 2 ) gave the desired product* 1.50 g. 80.2 %). 'h NMR (CD,OD): 8 6.65
(m. 2H), 6.55 (l, IH), 2.58 (l, 2H), 1.61 (m, 2H), 0.96 ft. 3H).
preparation of N-[2-hydroxy-3-n-propylphenyll-N'-[2-bromophenyl| urea
N-f2-Hydroxy-3-n-propyl phenyl]-N'-[2-bromo phenyl] urea was prepared from 2-
am,no-6-n-propyl phenol (302mg, 2.00 mmol) according to the procedure in General Method
B. The product was purified by precipitation from methylene chloride/ hcxancf l/20> and
liltering. (640mg,92%). 'H NMR (CD,OD): 8 8.(K) (d, IH), 7.58 (d. 1H). 7.32 (i. IH).
7.26 (t, IH), 6.96 (dd, IH), 6.89 (t, IH), 6.78 (d, IH).
Example 97
Preparation Of N^-hydroxv^-ethvlnhenvM . N-f 2-hmmnph»n Y l) ^
a) Preparation of 2-nitro-5-ethylphenol
3-ethylphenoI (5.00g, 41 mmol) was dissolved in methylene chloride(4() mL) followed
by the addition of sodium nitrate (3.83g, 45 mmol). The addition of sulfuric acid (50mL/ 3M)
was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was
allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and
extracted with water. The organic layer was dried over MgS0 4 and filtered. The solvent was
evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH,Cl->) gave
the desired product(1.7 g, 25 %). 'h NMR (CD3COCD,): 8 8.02 (d.lH). 6.99 (s.lH). 6 85
(d, IH), 2.69 (q, 2H), 1.30 (t, 3H).
b) Preparation of 2-amino-5-ethyllphenol
To a solution of 2-nilro-5-ethylphenol(lg, 6.4mmol) in melhanol(250mD was added
10% Pd/C ( 100 mg). The mixture was flushed with argon, then hydrogen was bubbled
through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon
pressure overnight. The mixture was filtered through celite and the eclue was washed with
methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel
(5%MeOH/ CH 2 CI 2 ) gave the desired produci(750 mg. 91 'H NMR (CD,OD): 8 6 41-
6.17 (m, 3H).
OPreparauon of N-[2-hydroxy-4-ethylphenyl]-N'-[2-bromophenyl| urea
N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromo phenyl) urea was prepared from 2- am.no-
5-cihylphenol (274mg. 2.00 mmol) according to the procedure in General Method B. The
product was purified by precipitation from methylene chloride/ hcxanc( 1/20 ) and filieniv
(520 mg. 77%). 'H NMR (CD,OD): 6 7.96 (d. IH). 7.62 (s. IH). 7.56 (d. IH). 7.30 u.
IH). 6.96 (t. IH). 6.82 (d. IH). 6.76 (d, IH).
Example 93
Preparation of N-|2-hydroxy 3-phenvlaminorarhonvl nh P n Y i i.N'-12-hr»mnnhnnvii U re :i
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a) Prcparalion of 2-nilro-6-phcnylaminocarbonylphcnol
2-Phenylaminocarbonylphenol (5.(K)g. 23 mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate (2.20g. 25.5 mmol). The addition
5 of sulfuric acid (3()mL/ 3M) was then made, followed by addition of a catalytic amount of
sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was
diluted with methylene chloride and extracted with water The organic layer was dried over
MgS0 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on
silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired product(2.5() g. 42 c 7< ). ! H NMR
10 (CD3COCD 3 ): 5 8.15 (d.lH), 8.09 (d.lH). 7.51 (d. 1H). 7.30 (d. 1 H). 7.10 (t. 1H). 7.01 (i.
1H).
b) Preparation of 2-amino-6-phenylaminocarbonylphenol
To a solution of 2-nitro-6-phenylaminocarbonylphenol (lg. 4.0 mmol) in
methanol(250mL) was added 10%.Pd/C (100 mg). The mixture was Hushed with argon, then
15 hydrogen was bubbled through the solution for 10 mm. and a hydrogen atmosphere was
maintained at balloon pressure overnight. The mixture was filtered through celite and the celuc
was washed with methanol. The solvent was evaporated and chromatography of the resulting
solid on silica gel (5%MeOH/ CH 2 C1 2 ) gave the desired producl(80() mg, 91 %). 'H NMR
(CD,OD): 5 7.73-7.57 (m, 2H), 7.43-7.27 (m, 3H), 7.25-7.10 (m. 1H). 6.94 (t. 1H). 6.74
20 (l, 1H).
c) Preparation of N-[2-hydroxy 3-phenylaminocarbonyl phenyll-N'-|2-bromophenyl) urea
N-[2-hydroxy 3-Phenylaminocarbonyl phenyl]-N'-[2-bromo phenyl] urea was
prepared from 2-amino-6-phenylaminocarbonylphcnol (456mg. 2.00 mmol) according to the
procedure in General Method B. The product was purified by precipitation from methylene
25 chloride/ hexane(l/20) and filtering. (800mg.94<7r ). 'H NMR (CD.OD): 'H NMR (CD.ODk
5 25 (d, 1H), 7.94 (d. 1H). 7.75-7.57 (m. 4H). 7.48-7.30 (m. 3H). 7.21 (l. 1H). 7.02 (dd.
1H), 6.92 (l, 1H).
Example 94
30 Preparation of N-l2-hvdroxv-3-cvano-4-mcthvlphcnvll-N '-f2-hromonhcnvl I urea
a) Preparation of the 2-nitro 5-methyl 6-bromo phenol
A solution of t-butyl amine(6.88 mL. 4.79 g. 2 equiv.) in methylene chloride was
treated with bromine ( 1 .67 mL. 5.2 g. 1 equiv.) at -20 "C. The flask was then cooled to -78
U C and the the 2-nilro 5-melhyl 6-bromo phenol (5 g. 1 equiv.. in methylene chloride) was
35 added drop-wise with vigrous stirnng. The reaction mixture was slowly warmed to -30 "C lor
1 h. then to - 10 °C for 2 hours. The reaction mixture was then partitioned between methylene
chloride and 5% aqueous acetic acid. The organic "layer was dried over magnesium sulfate,
filtered and concentrated in vacuo. The reaction mixture was purified by flash
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chromatography(Ethyl acetate/ hexancs) to remove dibrominated species. The 2-nitro 4-bromo
5-methyl phenol was then selectively crystallized out of methylene chloride. A final silica gel
column(5%eihyl acetate/ hexancs) yielded desired isomer in 90% punty.f 1.05 g. 14%). 'H
NMR (CDCI3): 6 7.95 (d, 1H, J = 10.0 Hz), 6.91 (d. 1H. J = 10.0 Hz). 2.52 (s, 3H).
5 b) Preparation of 2-nitro-5-methyl-6-cyanophenol
2-Nitro-5-methyl-6-bromophenol (100 mg, 0.433 mmol) was dissolved in dimethyl
formamidc (2mL) followed by the addition of triethylamine (0.175g, 1.73 mmol). The
addition of a catalytic amount dimethylamino pyridine was then made, followed by addition of
copper (I) cyanide (155mg, 1.73mmoI). The mixture was allowed to stir at 80°C for 4 hours.
10 The solvent was evaporated and chromatography of the resulting solid on silica gel (2 6 7cMeOH/
CH 2 C1 2 ) gave the desired product (70 mg. 91 9c). 'H NMR (CD3COCD,): 5 8.30 (d. 1H),
7.15 (d,lH), 2.61 (s, 3H).
c) Preparation of 2-amino-5-melhyl 6-cyanophenol
A mixture of 5-cyano-2-nitrophenol(70 mg, 0.39mmol) and tin (II) chloride (265 mg.
15 1 . 1 8mmol) in ethanol(20mL) was heated at 80°C under argon. After 2 hours, the starting
material has disappeared and the solution was allowed to cool down and then poured into ice.
The pH was made slighUy basic (pH7-8), by addition of solid NaOH. before being extracted
with ethyl acetate. The organic phase was washed with brine, dried over MgS0 4 and filtered.
The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/
20 CH 2 C1 2 ) gave the desired product(175 mg, 86 %). l H NMR (CD.OD): 8 6.87 (d, IH). 6.75
(d.lH). 6.32 (s. 3H).
d) Preparation of N-[2-hydroxy 3-cyano 4-methyl phenyl |-N'-[2-bromophenyl] urea
N-|2-hydroxy 3-cyano 4-mcthyl phenyl|-N'-|2-bromophcnyl] urea was prepared from
2-amino-5-mcthy]-6-cyano phenol (50mg, 0.34 mmol) according to the procedure in General
25 Method B The product was purified by precipitation from methylene chloride/ hcxane( 1/20)
and filtering. (70mg. 6()<7r). 'H NMR (CD 7 OD): 5 7.92 (d. 1H). 7.68 (d. 1H). 7.59 (d. IH).
7.31 (t. IH). 7.00 (t. IH). 6.62 (t. IH). 2.49 (s, (3H).
Example 95
30 Preparation of N-12-hvdroxv 4-Car boxvnhenvl nhenvl l-N"-[2-bromonhen\ 1 1 ure;i
a)Preparaiion of 4-nitro-3-hydroxybcnzophenonc
3-Hydroxybenzophenonc (3.00g, 15. 1 mmol) was dissolved in methylene
chloridc(40mL) followed by the addition of sodium nuraie ( 1.42g. I6.7mmol). The addition
of sulfuric acid (25mL/ 3M) was then made, followed by addition of a catalytic amount of
35 sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was
diluted with methylene chloride and extracted with water. The organic layer was dried over
MgS0 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on
silica gel (4<-7rMeOH/ CH 2 C1 2 ) gave the desired producK 1 . 10 g. 30%). 'H NMR
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(CD3COCD,): 6 8.25 (d.lH). 7.86 (d.lH). 7.71 (m. IH). 7.59 (d. 1H). 7.48 (s, IH). 7.39
(dd, IH).
b)Prcparaiion of 4-amino-3-hydroxybenzophenone
A mixture of 4-nuro-3-hydroxybenzophenone (900 mg, 3.7mmol) and tin (II) chloride
5 (2.5 g. Ill mmol) in cthanol(50mL) was heated at 80°C under argon. After 2 hours, the
starting material has disappeared and the solution was allowed to cool down and then poured
into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being
extracted with ethyl acetate. The organic phase was washed with bnne, dried over MgS0 4 and
filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel
10 (4%MeOH/ CH 2 C1 2 ) gave the desired product(685 mg, 87 %). 'h NMR (CDiOD): 5 7.65 (d,
2H), 7.55 (d.lH), 7.49 (t, 2H). 7.26 (s, IH), 7.16 (dd, IH), 6.68 (d, IH).
^Preparation of N-[4-Carboxyphenyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
N-[4-Carboxyphenyl-2-hydroxyphenyll-N'-[2-bromophenyl] urea
was prepared from 4-amino-3-hydroxybenzophenone (330mg, 1.5 mmol) according to the
1 5 procedure in General Method B. The product was purified by precipitation from methylene
chloride/ hexane(l/20) and filtering. (490mg ? 79%). 'h NMR (CD-.OD): 5 8.40 (d, IH),
8.09 (d, IH), 7.83 (d, 2H), 7.65-7.60 (m, 4H), 7.48 (s, IH), 7.43 (d, IH), 7.35 (d, (IH),
7.10 (1.1H).
20 Example 96
Preparation of N-[2-hvdroxv 3-carhoxv phenvl nhnny]l-N'-12-hromophenvll urea
a) Prcparation of 3-nitro-2-hydroxybenzophenone
2-Hydroxybcnzophenonc (3.00g, 15. 1 mmol) was dissolved in methylene
chlonde(4()mL) followed by the addition of sodium nitrate (1 42g. 16.7mmol). The addition
25 of sulfuric acid (25mL/ 3M) was then made, followed by addition of a catalytic amount of
sodium nitntc. The mixture was allowed to stir. Al ter 24 hours, the reaction mixture was
diluted with methylene chloride and extracted with water. The organic layer was dried over
MgSO,, and filtered. The solvent was evaporated and chromatography of me resulting solid on
silica gel (4<7rMeOH/ CH ; C1 : ) gave the desired product(1.60 g. 44 <7o. 'H NMR
30 (CD3COCD,): 6 8.30 (d.lH). 7.86 (m.3H), 7 71 (m. IH). 7.78 (d. IH). 7.56 (dd 2H). 7.24
(t. IH).
b) Preparation of 3-amino-2-hydroxybenzophenonc
A mixture of 3-niiro-2-hydroxybenzophcnone (600 mg. 2.5mmol) and tin (II) chloride
1 1.7 g, 7.5mmol) in cthanol(50mL) was heated at 8()°C under argon. Alter 2 hours, the
35 starting material had disappeared and the solution was allowed to cool down and then poured
into ice. The pH was made slightly basic (pH7-8). by addition of solid NaOH. before being
extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS0 4 and
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filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel
(4%MeOH/ CH 2 CI 2 ) gave the desired product(490 mg, 92 %). 'H NMR (CD 3 OD): 5 7.65-
7.40 (m, 5H). 6.98 (d,lH), 6.86 (d, 1H), 6.67 (t. 1H).
c)Preparation of N-J2-hydroxy 3-carboxyphcnyl phenyI]-N'-[2-bromophenyl] urea
5 N-|2-hydroxy 3-carboxyphenyl phenyl ]-N'-[2-bromophenyl] urea was prepared from
3-amino-2-hydroxybcnzophenone (250mg, 1.20 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/ hexane( 1/20)
and filtering. (20(>mg, 78*). *H NMR (CD,OD): 5 8.35 (d, 1H), 7.96 (d, 1H). 7.72 (d.
2H), 7.65-7.50 (m, 4H), 7.35 (d. 1H). 7.30 (d, 1H), 7.01 (dd. (1H). 6.92 (t. 1H).
10
Example 97
Preparation of N-r2-hvdroxv 3-henz.vlox y nhenvll-N'-r2-hromophenvH urea
a) Preparation of 2-nitro-6-benzyloxy phenol
2-Benzyloxyphenol (5.00g. 2S.0mmol) was dissolved in methylene chloride(40mL)
15 followed by the addition of sodium nitrate (2.30g, 27.5mmol). The addition of sulfuric acid
(31mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The
mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene
chloride and extracted with water. The organic layer was dried over MgS0 4 and filtered. The
solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/
20 CH2CI2) gave the desired product(2.6 g. 43 %). 'H NMR (CD3COCDO: 5 7.70 (d.lH).
7.50-7.28 <m. 5H), 7.14 (d. 1H). 6.92 (t. 1H), 5.21 (s. 2H).
b) Preparation of 2-amino-6-benzyloxy phenol
A mixture of 2-mirn-6-bcnzyloxy phenol (1.00 g, 4.10mmol) and tin (II) chloride
(2.75 g. 12.2 mmol) in ethanoK 1 5()mL) was heated at 80°C under argon After 2 hours, the
25 starting material had disappeared and the soluuon was allowed to cool down and then poured
into ice The pH was made slightly basic (pH7-8). by addition of solid NaOH. before being
extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS0 4 and
filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel
(4<7cMeOH/ CH 2 C1 2 ) gave the desired producl(1.35 g. 88 c 7< ). 'H NMR (CDiOD): 57.46 (d.
30 2H). 7.40-7.35 <m. 5H). 6.55 (d. 1H), 6.40 (d. IH). 5.10 (s. 2H).
b)Preparation of N-[2-hvdroxy3-benzyloxy phenyll-N'-[2-bromophenyl] urea
N-[3-bcn/.yloxy-2-hydroxyphenyl)-N , -f2-bromophenyI] urea was prepared from 2-
niiro-6-ben/.vloxy phenol (430mg. 2.00 mmol) according to the procedure in General Method
B. The product was purified by precipitation from methylene chloride/ hexane( 1/20) and
35 filtering. (630mg. 76% ). *H NMR (CD^OD): 5 7.93 (d, IH), 7.58 (d. 1H). 7.54-7.42 (m.
3H). 7.40-7.25 (m. 4H). 7.00 (t. IH). 6.69 (d. 2H). 5.16 (s. 2H).
Example 98
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Preparation of N-3-f2-hvdro xv-5-indanonel-N , -f2-hromonhonvll nr^.
a) Prcparation of 2-hydroxy-3-nitro-5-indanone
2- Hydroxy-5-indanone(3.00g, 2().0mmol) was dissolved in methylene chloride(4()mL)
followed by the addition of sodium nitrate (1.95g, 21.0mmol). The addition of sulfuric acid
5 (25mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The
mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene
chloride and extracted with water. The organic layer was dried over MgS0 4 and filtered The
solvent was evaporated and chromatography of the resulting solid on silica gel (49J.MeOH/
CH 2 C1 2 ) gave the desired product(1.5 g, 39 %). 'h NMR (CD^COCD,): 5 7.70 (d.lH), 7.04
10 (d. 1H), 3.04 (d, 2H). 2.74 (d, 2H).
b) Preparation of 3-amino-2-hydroxy-5-indanone
A mixture of 2-hydroxy-3-nitro-5-indanone (1.50 g, 7.80mmol) and tin (II) chloride
(5.25 g. 23.3 mmol) in ethanol(150mL) was heated at 80°C under argon. After 2 hours, the
starting material had disappeared and the solution was allowed to cool down and then poured
1 5 into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being
extracted with ethyl acetate. The organic phase was washed with brine, dried over MgS0 4 and
filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel
(4%MeOH/ CH 2 C1 2 ) gave the desired product( 1 00 g, 79 %). 'H NMR (CD 3 OD): 5 6.85
(d.lH), 6.45 (d, 1H), 2.95 (d, 2H), 2.60 (d, 2H).
20 e)Preparauon N-3-[2-hydroxy-5-indanone]-N'-[2-bromophenyl] urea
N-(2-Hydroxy-5-indanone]-N'-[2-bromophenyl] urea was prepared from 3-amino-2-
hydroxy-5-indanone (326mg, 2.00 mmol) according to the procedure in General Method B.
The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering
(61()mg. 85%). 'H NMR (CD.OD): 5 7.92 (d. 1H). 7.65 (m. 2H). 7.45 (t. 1H). 7.09 (i.
25 1H). 7.00 (d. 1H), 2.90 (d. 2H). 2.66 (d. 2H).
Example 99
Preparation of CE)-N-[4-r2-(Methoxvcarbonv1) ethenvll-2-hvdroxvphenvll-N'-l2-
bromophenvli urea
30
a)Prcparation of 4-nilro-3-hydroxycinnamic acid
3- Hvdroxycinnamic acid (3.00g, 18.3 mmol ) was dissolved in methylene
chk>ndc(40mL) followed by the addition of sodium nitrate (1 .70 g. 26. 1 mmol). The addition
of sulfuric acid (25 mL/ 3M) was then made, followed by addition of a catalytic amount of
35 sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was
diluted with methylene chloride and extracted with water. The organic layer was dried over
MgS0 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on
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silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired producK 1 .0 g. 26 ). 'h NMR (CD^COCD.)
5 8.07 (d, 1H), 7.69 (d. 1H), 7.51 (s, 1H), 7.46 (d, 2H). 6.75 (d.lH).
b) Preparation of 4-nitro-3-hydroxymethylcinnamate
4-Nitro-3-hydroxycinnamic acid was stirred in excess methanol with a catalytic amount
of sulfuric acid. The solvent was evaporated and chromatography of the resulting solid on
silica gel (4<7rMeOH/ CH 2 CI 2 ) gave the desired producK 1 .0 g, 94 9c). 'h NMR (CD,COCD-,>-
8 8.17 (d, 1H), 7.69 (d, 1H). 7.52 (s, 1H). 7.45 (d, 2H), 6.75 (d.lH). 3.80 (s. 3H)
c ) Preparation of 4-amino-3-hydroxymethylcinnamate
A mixture of 4-nitro-3-hydroxymethylcinnamate ( 1.0 g. 4.5()mmol) and tin (II)
chloride (3.0 g. 13.4 mmol) in ethanol(50mL) was heated at 80°C under argon. Alter 2 hours,
the starting material had disappeared and the solution was allowed to cool down and then
poured into ice. The pH was made slightly basic (pH7-8). by addition of solid NaOH. before
being extracted with ethyl acetate. The organic phase was washed with brine, dried over
MgSO« and filtered. The solvent was evaporated and chromatography of the resulting solid on
silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired product (650 mg, 75 'H NMR (CD,OD)-
57.50 (d.lH), 6.94 (s, 1H), 6.89 (d, 1H), 6.68 (d, 1H), 6.18 (d, 1H). 3.74 (s, 3H).
d) Preparation (E)-N-f4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-f2-
bromophenyl] urea
(E)-N-[4-[2-(Methoxycarbonyl) ethenyI]-2-hydroxyphenyl)-N-f2-bromophcnyl | urea
was prepared from 4-amino-3-hydroxymethyIcinnamate (250mg, 1.3 mmol) according to the
procedure in General Method B. The product was purified by precipitation from methylene
chloride/ hexane(l/20) and filtering. (3()()mg. 59%). 'h NMR (CD,OD): 8 8.24 (d.lH). 8.05
(d. 1H), 7.69 (d. 1H). 7.65 (d. 1H), 7.42 (i. 1H). 7.21 (s. 1H). 7.19 (d. 1H). 7.10 (t. 1H>
6.45 (d.lH) 3. SI (s. 3H).
Example 100
Preparation of (E)-N-f 3-12-f Methnxyrar h onvn eihpnvll-2-hvrin^ vphenvll-N-f?-
bromophenvll urea N' -r2-hromophfinvl 1 nr^
a)Preparation oi 3-nitro-2-hydroxycinnamic acid
2-Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene
chloride(4()mL) followed by the addition of sodium nitrate (2.2 1 g. 26. 1 mmol). The addition
of sulfuric acid (30 mU 3M) was then made, followed by addition of a catalytic amount of
sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was
diluted with methylene chloride and extracted with water. The organic layer was dried over
MgS0 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on
silica gel (4%MeOW CH 2 C1 2 ) gave the desired product(2.0 g. 52 ?<). 'h NMR (CD,COCD .)
5 8.21 (d. 1H). 8.16 (d. 1H). 8.05 (d. 1H), 7.19 (t, 1H). 6.72 (d. 1H)
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b) Preparation of 3-nitro-2-hydroxymethylcinnamate
3-nuro-2-hydroxycinnamic acid was stirred in excess methanol with a catalytic amount
of sulfuric acid. The solvent was evaporated and chromatography of the resulting solid on
silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired producl( 1 .0 g. 94 9? ). 'h NMR (CD,COCD,):
5 5 8.25 (d, 1H), 7.8.15 (d, IH), 8.06 (s, 1H). 7.20 (t, 2H), 6.76 (d.lH). 3.80 (s. 3H).
c) Preparation of 3-amino-2-hydroxymethylcinnamaie
A mixture of 3-nitro-2-hydroxymethylcinnamate (1.0 g, 4.5 mmol; and tin (II) chloride
(3.0 g. 13.4 mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours, the
starting material had disappeared and the solution was allowed to cool down and then poured
10 into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH. before being
extracted with ethyl acetate. The organic phase was washed with bnne. dried over MgS0 4 and
filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel
(4%MeOH7 CH 2 C1 2 ) gave the desired product (700 mg, 81 %). 'H NMR (CD-.OD): 5 8.04 (d.
IH), 6.93 (d, 1H),6.79 (d, 1H), 6.71 (t, 1H), 6.43 (d, IH), 3.72 (s, 3H).
15 d)Preparation(E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-(2-bromophenyl |
urea
(E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[ 2-bromophenyl 1 urea
was prepared from 3-amino-2-hydroxymethylcinnamate (100 mg, 0.52 mmol) according to the
procedure in General Method B. The product was purified by precipitation from methylene
20 chloride/ hcxane(l/20) and filtering. (150mg, 74%).'h NMR (CD,OD): 5 8.10 (d.lH). 8.00
(d. IH), 7.69 (d, IH), 7.65 (d, IH), 7.42 (t, IH), 7.38 (l. IH). 7.32 (d. IH). .7.05 (t. IH)
6.55 (d.lH) 3.81 (s, 3H).
Example 101
25 Preparation of (E)-N-f3-f2-(Aminocarhonvn ethenvll-2-hvdroxvphcnvll-N'-l2-hromoprienvll
urea N'-f2-bromophenvn urea
a")Preparalion of 2-hydroxycinnamide
2-Hydroxycinnamic acid (2.00g, 12.3 mmol) was dissolved in dimethyl
formamide( lOmL) followed by the addition of benzotnazol- 1 -yloxy-
30 tris(dimethylamino)phosphonium hexafluorophosphaie (5.4g. 12.3 mmol) and trielhvlamme (
1.7mL. 12.3mmol). Ammonia gas was bubbled into the reaction mixture for 30 minutes. The
mixture was allowed to stir for 24 hours, the reaction mixture was diluted with methylene
chloride and extracted with water. The organic layer was dried over MgSCX, and filtered The
solvent was evaporated and chromatography of the resulting solid on silica gel (49? MeOH/
35 CH 2 C1 ; ) gave the desired producl( 1 .5 g, 75 %).
b)Preparation of 3-nilro-2-hydroxycinnamide
2-Hydroxycmnamide (750 mg. 4.6 mmol) was dissolved in methylene chlonde(40mL)
followed bv the addition of sodium nitrate (430 mg, 5. lmmol). The addition of sulfuric acid
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(7 mL/ 3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The
mixture was allowed to stir. Alter 24 hours, the reaction mixture was diluted with methylene
chloride and extracted with water. The organic layer was dried over MgS0 4 and filtered. The
solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/
5 CH 2 C1 2 ) gave the desired product(350 mg, 36 7c). 'H NMR (CD3COCD 3 ): 5 8.19 (d, 1H).
8.02 (d. 1H). 7.88 (d. 1H). 7.15 (t, 1H), 6.84 (d. I H)
c)Preparation of 3-amino-2-hydroxycinnamidc
A mixture ol 3-nitro-2-hydroxymcthyicinnamaie (350 mg. 1.7 mmol) and tin (II)
chloride (3.0 g. 13.4 mmol) in eihanol(50mL) was heated at 80°C under argon. After 2 hours.
10 the starting material had disappeared and the solution was allowed to cool down and then
poured into ice. The pH was made slightly basic (pH7-8). by addition of solid NaOH. before
being extracted with ethyl acetate. The organic phase was washed with brine, dried over
. MgS0 4 and filtered. The solvent was evaporated and chromatography of the resulting solid on
" silica gel (4<7rMcOH/ CH 2 C1 2 ) gave the desired product(244 mg.80%).
15 d)Preparation of (E)-N-[3-[2-(Aminocarbonyl) eihenyl]-2-hydroxyphenyl]-N'-[2-
bromophcnyl] urea
(E)-N-[3-[2-(Aminoearbonyl) ethcnyl]-2-hydroxyphenyl]-N'-f2-bromophenyl] urea
was prepared from 3-amino-2-hydroxyeinnamide (100 mg, 0.56 mmol) according to the
procedure in General Method B. The product was purified by precipitation from methylene
20 chloride/ hexanc(l/20) and filtering. (1 10 mg, 52%).'H NMR (CD.OD): 8 8.00 (d.lH), 7.90
(d. 1H). 7.63 (d. 1H). 7.55 (d. IH). 7.35 (m. 2H), 7.05 (l. 1H). 6.95 (t. 1H). 6.70 (d.lH)
Example 102
Prenaration of (E)-N-l4-l2-(Aminocar honvl ) cthcnvll-2-hvriroxvnhenvll-N'-l2-hromophen\ i 1
25 urea N'-f2-hromophcnvll urea
a)Preparalion of 3-hydroxycinnamidc
3-Hydroxvcinnamic acid (2.00 g. 12.3 mmol) was dissolved in dimethyl lormamidel Ki
mL) followed by the addition of ben/otria/ol- 1 - yloxy-tris(dimclhylamino)phosphonium
hcxafiuorophosphaic (5.4g. 12.3 mmob and triclhylaminc ( 1.7 mL. l2.3mmol). Ammonia
30 gas was bubbled into the reaction mixture lor 30 minutes. The mixture wa.s allowed to sin loi
24 hours, the reaction mixture was diluted with methylene chloride and extracted with watci
The organic layer wa.s dried over MgSC and filtered. The solvent wa.s evaporated and
chromatography of the resulting soiid on silica gel (4%McOH/ CH 2 C1 2 ) gave the desired
producK 1.3 g. 65 L 7< ).
35 b)Preparalion ol 4-nitro-3-hydroxycinnamide
3-Hydroxycinnamide (750 mg. 4.6 mmol) was dissolved in methylene chloride(40 mL)
followed by the addition ol sodium nitrate (430 mg. 5.1 mmol). The addition of sulfuric acid
(7 mL/ 3M ) was then made, followed by addition of a catalytic amount of sodium nitrite. The
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mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene
chloride and extracted with water. The organic layer was dncd over MgS0 4 and Tillered The
solvent was evaporated and chromatography of the resulting solid on silica gel (4%McOH/
CH 2 CI 2 ) gave the desired producl(24() mg, 25 %). 'H NMR (CD^COCDO: 6 8.09 (d. 1H).
5 7.49 (d. IH). 7.26 (s, 1H). 7.16 (d, IH), 6.71 (d, 1H)
c) Prcparation of 4-amino-2-hydroxycinnamide
A mixture of 4-nitro-3-hydroxymethylcinnamate (300 mg. 1 .40 mmol) and tin (II)
chloride (980 mg, 4.30 mmol) in cthanol(50 mL) was heated at 8()°C under argon. After 2
hours, the starting material had disappeared and the solution was allowed to cool down and
10 then poured into ice. The pH was made slightly basic (pH 7-8). by addition of solid NaOH.
before being extracted with ethyl acetate. The organic phase was washed with brine, dried
over MgSCX, and filtered. The solvent was evaporated and chromatography of the resulting
solid on silica gel (4%MeOH/ CH 2 C1 2 ) gave the desired product (200 mg. 74 %).
d) Prcparation(E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl)-N'-f2-bromophenylj
1 5 urea
(E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl| urea
was prepared from 4-amino-2-hydroxycinnamide (lOOmg. 0.56 mmol) according to the
procedure in General Method B. The product was purified by precipitation from methylene
chloride/ hexane(l/20) and filtering. (I25mg. 54%). *H NMR (CD,OD): 5 8.05 (d.lH). 7.92
20 (d, IH). 7.60 (d, 1H), 7.4 5 (d. 1H), 7.35 (I, IH), 7.05 (m, 2H). 6.50 (d.lH) .
Example 103
Preparation of N-12-hvdroxv 4-(phenvl amino carhoxv) phenyl l-N' -l 2-hromophcnvH urea
N-|2-hydroxy 4-(phcnyl amino carboxy) phenyl|-N'-[2-bromophenyl| urea was
25 prepared from 5-(phcnyl amino carboxy) 2-amino phenol (0.50 mmol) according to the
procedure in General Method B. The product was purified by precipitation from methylene
chloride/ hcxanc( 1/20) and filtering. (150 mg, l() c 7< ). 'h NMR (CD.OD): 6 8.25 (d. IH).
8.00 (d. IH). 7.75 (d. 2H). 7.64 (d. IH). 7.50 (d. 2H). 7.41 (m. 3H). 7.16 u. IH). 7.05 (i.
IH)
30
Example 104
Preparation of N-l4-aminocarhonvl-2-hvdroxvphenyl l-N"-l2-hromophcnvll urea
N-|4-Aminocarbony] -2-hydroxyphcnyl]-N'-|2-bromophcn\i| urea was prepared trom
5-aminocarbonyl-2-amino phenol (304 mg, 0.50 mmol) according to the procedure in General
35 Method B. The product was purified by precipitation from methylene chloride/ hcxanet 1/20)
and filtering. (440 mg. 627, ). 'H NMR (CD^OD): 5 8.09 (d. IH). 7.91 (d. lH).7.60(d.
IH). 7.45 tm. 3H). 7.00 (d. IH).
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Example 105
Preparation of N-(2-Hvdroxv-3 .S 6-tr i nuor()phcnvl)-N^(2-hmmonhrnvn.irr^
N-(2-Hydroxy-3,5,6-trinuorophenyl)-N -(2-bromophenyl)urea was prepared from
3.5.6-irinuoro-2-hydroxyaniline (83 mg, 0.51 mmol) and 2-(bromophenyl)isocyanatc ( 100
mg, 0.53 mmol) according to the procedure in General Method B. The product was purified
by preparation thin layer chromatography. EI-MS m/z 359 (M-H)\
Example 106
Preparation Of N-f2-Hvdroxv-3-nuoro-4-trinuoromptt 1 vlnhenvn-N , -(2-hromophPnvn,.rPn
N-(2-Hydroxy-3-lluoro-4-trinuoromethylphenyl)-N , -(2-bromophenyl)urea was
prepared from 4-trinuoromethyl-3-nuoro-2-hydroxyaniline (239 mg. 1.2 mmol) and 2-
(bromophenyl)isocyanate (243 mg, 1.2 mmol) according to the procedure in General Method
B. Removal of solvent under reduced pressure and chromatography of the resulting solid on
silica gel (hexane:ethyl acetate) gave the title compound (20 mg. 49c). EI-MS m/z 391 (M-H)
Examnle 107
Preparation of N-(2-Hvdroxv-3-indn p henvlVNV?-hromophpnvl W fl
N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea was prepared from 3-iodo-2-
hydroxyaniline (200 mg. 0.85 mmol) and 2-(bromophenyl)isocyanaic (169 mg, 0.85 mmol)
according to the procedure in General Method B. Removal of solvent under reduced pressure
and chromatography of the resulting solid on silica gel (hexane:ether) gave the tide compound
(40 mg. U9F). 'HNMR (DMSO): 6 9.45 (s, 1H). 9.15 (s. 1H). 8.8 (s. 1H). 7.95 (d. 1H).
7.8 (d. 1H).7.65 (d. 1H). 7.4 <d. 1H), 7.3 (t. IH). 7.0 (t. 1H). 6.65(1. 1H).
Example 108
Preparation of N-I2-I fl2-(triniior omethvnphenvl Isulfonvl laminoiphenvl l-N'-f?-
bromophenvDurea
a) Prcparation of I2-[2-(tnnuoromethy])phenyl|(.sulfonamido)aniline)
The title compound was prepared according to General Method C usine 2-
(trinuoromethyl)bcnzenesull'onyl chloride ( 1 cquiv.) The product was purified by
chromatography on silica gel (methylene chloridc:mcthanoI) (1.04 g. ?V7< ). EI-MS m/z 317
(M+H)*.
b) Prcparation of N-|2-[||2-(trinuoromethyl)phcnyl)sulfonyl|amino|phen\i|-N'-(2-
hromophcnyl)urea
The title compound was prepared using[2-|2(trilluoromeihyl)phenyl]
(sullonamido)aniline ( 1 .04 g. 3.2 mmol) and 2-(bromophenyl)isocyanatc (652 mg. 3.2 mmol >
according to General Method B. The solvent was evaporated to give the desired urea ( 1 .03 n.
6\9f). EI-MS m/z 5 14 (M+HT.
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Example 109
Preparation of N-(2-Bromophenyl)-N'-f2-dimethylaminosulfonvlaminolphcnvllurea
a) Preparalion of [2-[ 1 J-(dimcihylamino)]sulfonamidoaniline]
The title compound was prepared according to General Method C using
dimethylsulfamoyl chloride ( 1 equiv.). The product was purified by chromatography on silica
gel (methylene chloride:methanol). ES-MS m/z 216 (M+H)*.
b) Preparation of N-(2-Bromophenyl)-N'-[2-(dimethylaminosulfonylamino|phenyl]urca
The title compound was prepared from [2-[ l.Wdimethlyaminoisulfonamido-
aniline (137 rag. 0.6 mmol) and 2-(bromophenyl)isocyanate (126 mg. 0.6 mmol) according to
General Method B. The solvent was evaporated and chromatography on silica gel (ethyl
acetate :hexane) gave the desired urea. EI-MS m/z 413 (M+H)*
Example 110
Preparation of N-f2-0?henethvlsulfonvlamino) phenvn-N'-(2-hromophcnvl)urea
[2-(Phenethylsulfonamido) aniline] (example 60, 300mg, 1.09 mmol) was placed in a
Parr shaker bottle containing palladium ( 1 80 mg) under an argon stream. Methanol ( 1 50 mL)
was added and the container placed on a Parr shaker (55 psi) for several hours. The reaction
mixture was filtered through Celite and the filtrate was evaporated to give the desired aniline
(269 mg. 90%). EI-MS m/z 277 (M+Hf.
b)Preparation of N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urca
The title compound was prepared from [2-(phcneihylsulfonamido) aniline | (269 mg.
0.97 mmol) and 2-(bromophenyl)isocyanalc ( 193 mg. 0.97 mmol) according to General
Method B. The desired urea was precipitated out of toluenc/hcxanc (3S4 mg. 7H9r ). EI-MS
m/z 472 (M-H)
Example 1 1 1
Preparation of N-12-l(2-acetamido-4-methvlthiazol-5-vl)sulfonylaminolphcnvllrN'-(2-
hromophenyPurea
a) Prcparation of [2-[(2-acetamido-4-mcthyl-5-ihiazole)sulfonamido]aniline|
The title compound was prepared using 2-acctamido-4-mcihyl-5-ihiazolesulfonyl
chloride ( 1 equiv. ) according to General Method C. A solid precipatated from the reaction
mixture and was filtered to give the desired aniline ( 1.68 g. 529< ). ES-MS m/z 327 (M+HT
b) Prcparation of N-[2-[(2-acciamido-4-methylihiazo]-5-yl)sulfonylamino|pheny!|-N'-(2-
bromophenyDurea
The title compound was prepared from [2-[(2-acetamido-4-mcthyl-5-
thiazole)sulfonamidolaniline] (1.68 g.5.14 mmol) and 2-(bromophenyl)isocyanatc
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(1 .02 g, 5. 14 mmol) according to General Mcihod B The product was precipitated from ethyl
acetate/hexanc (220 mg, H%). EI-MS m/z 524 (M+H)\
Example I 1 7
5 Preparation of N-l2-hvdroxv-4-cvarionhenvll- N-l4-phnnvlphenvll urc-.x N-(2-Hydroxy-4-
cyanophenyl]-N'-[4-phenylphenyl] urea was prepared from 2-amino-5-cyanophenol (6()mg.
0.45 mmol) according to the procedure in Genera) Method B. The product was purified by
precipitation from methylene chloride/ hcxane(l/20) and filtering. (135 mg. 75«7r ). 'H NMR
(CD ? OD): 5 8.33 (d, IH), 7.71-7.29 (m. 9H), 7.25 (d. IH). 7.12 (s. I H).
10
Example 1 1 3
Preparation of N-r2-hvdroxv-4-cvannphen vH-N'-r2 . Vdichlornphrnvl I hfpa
. N-[2-Hydroxy-4-cyanophenyl]-N , -(2,3 dichlorophenyl) urea was prepared from 2-
amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B
15 The product was purified by precipitation from methylene chloride/ hcxane( 1/20) and filtering.
(125mg, 86%). 'H NMR (CD,OD): 5 8.27 (d, IH), 8.15 (m, IH). 7.39-7.20 (m. 2H). 7.16
(d. IH), 7.06 (s. IH).
Example 1 14
20 Preparation of N-f2-hvdroxv-4-cvann phenvll-N , -f2-methnxvphenvll urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl) urea was prepared from 2-
amino-5-cyanophenol (6()mg, 0.45 mmol) according to the procedure in General Mcihod B
The product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering
(105mg, 83%). 'H NMR (CD.OD): 6 8.26 (d. IH). 8.02 (d. IH). 7 14 <d. IH). 7.05 <s.
25 IH). 7.00-6.83 (m. 3H), 3.84 (s. 3H).
Example 1 1 5
Preparatio n of N-l2-hvdroxv-4-cvanonhenvl l-N'-[3-mcthoxvphenyll urea
N-|2-Hydroxy-4-cyanophenyl|-N -|3-mcthoxyphcnyl| urea was prepared from 2-
30 amino-5-cyanophenol (6()mg. 0.45 mmol) according to the procedure in General Method B
The product was purified by precipitation from methylene chloride/ hcxane( 1/20) and fil terms:
(102mg. 809; ). 'H NMR (CD,OD): 8 X.25 (d. IH). 7.25-7 OS tm. 3H). 7.04 (s. IHi. 6 90
(l. IH). 6.58 (d. IH)
35
Example 1 16
Preparation of N-f2-h vdroxv-5-fluorophenvl l-N'-f 2-hromophenvl 1 uwa
a)Preparation of 2-amino-4-nuorophcnol
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A mixture oi 4-fluoro-2-mirophcnol( lg. 4.64mmol) and tin (II) chloride (5.4 g,
24.2mmol) in cthanol(50mL) was heated at 80°C under argon. Alter 2 hours, the starting
material had disappeared and the solution was allowed to cool down and then poured into ice.
The pH is made slightly basic (pH7-8). by addition of solid NaOH, before being extracted with
ethyl acetate. The organic phase was washed with brine, dried over MgS0 4 and filtered. The
solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/
CH 2 C1 2 ) gave the desired producl(622 mg. 85 6 7r). 'h NMR (CD,OD): 8 6.51 (dd. 1H). 6.32
(dd, IH), 6.17 (ddd. 1H).
b)Preparalion of N-[2-hydroxy-5-Huorophenyl|-N'-[2-bromophenyl] urea
N-[2-Hydroxy-5-fluorophenyl|-N'-[2-bromophenyl| urea was prepared from 2-amino-
6-fluoro phenol (254mg, 2 (X) mmol) according to the procedure in General Method B. The
product was purified by precipitation from methylene chloride/ hexane( 1/20) and filtering.
(520mg.80%). l H NMR (CD.OD): 5 7.88 (d, 1H), 7.79 (dd. IH). 7.57 (d, 1H), 7.31 (i.
1H). 7.00 (t. 1H). 6.76 (dd. IH). 6.57 (ddd.lH).
Examnle 1 17
Preparation of N-f2-hvdroxv-5-t rinuoromcthv]nhenvll-N , -t2-hrom(^nhenvll urea
a) Prcparation of 2-amino-4- trinuoromethylphenol
A mixture of 4-trifluoromcthyI-2-nitrophcnol( 1 .0 g. 4.8mmol) and tin (II) chloride (5.4
g, 24.2 mmol) in ethanol( 1 5()mL) was healed at 8()°C under argon. After 2 hours, the starting
material had disappeared and the solution was allowed to cool down and then poured into ice.
The pH was made slightly basic (pH7-8). by addition of solid NaOH. before being extracted
with ethyl acetate. The organic phase was washed with brine, dried over MgS0 4 and filtered
The solvent was evaporated and chromatography of the resulting solid on silica gel (4<* MeOH/
CH 2 C] ; ) gave the desired produci(7()K mg. 83 c 7<). ; H NMR (CD^OD): 6 6.87 (s. IH). 6. SO
(d. 1H). 6.69 (d, 1H).
b) Prcparation of N-f2-hydroxy-5-trinuoromcihylphcnyl |-N'-|2-bromophcnyl| urea
N-[2-hydroxy-5-irinuoromethylphcnyl|-N'-|2-biomophcnyll urea was prepared from
2-amino-4-irifluorornelhylphenol (354mg. 2.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hcxanc) lequn ./20cquiv.) and filtering. (490mg. 659; ). 'H NMR (CDiOD): 8 8.40 is. IH).
7.94 (d. IH). 7.60 (d. IH). 7.35 (t. IH). 7.18 (d. IH). 7.03 (l. IH). 6.95 (d. 1 H >
Example 1 1 8
Preparation of N-[2-hydroxyphcnvll-N'-l2-bromonhenvll urea
N-[2-hydroxyphcnyl]-N'-|2-bromo phenyl) urea was prepared from 2- amino-phenol
( 141mg. 1.30 mmol) according to the procedure in General Method B. The product was
purified by precipitation from methylene chloride/ hcxanc( 1/20) and filtering. (3(K)mc.75^ )
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'H NMR (CD,OD): 5 8.05 (d. IH). 7.49 (d. 1H). 7.25 it. 2H), 6.96 (i. IH). 6.
6. AX (I. IH)
Example 1 19
Preparation of N-(trans-3-sjyrl 2-hvdrox v nh envll-N'-n-hromonhflnvll .,m a
a) Prcparaiion of trans-6-styrI-2-nitrophenol
Trans-2-siyrlphcnol (500 mg, 2.55 mmol) was dissolved in methylene ehlor.de(40mL)
followed by the addition of sodium nitrate (240 mg, 2.81 mmol). The addition of sulfuric acid
(3 mL of 3M ) was then made, followed by addition of a catalytic amount of sodium nitrite.
The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with
methylene chloride and extracted with water. The organic layer was dried over MgS0 4 and
filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel
(4%MeOH/ CH 2 CI 2 ) gave the desired product (200 mg, 36 %). 'H NMR (CD3COCDO: 6
8.05 (d. IH). 7.90 (d. 2H).7.65-7.20 (m,7H).7.00 (t,lH).
b) Preparation of trans-6-styrl-2-aminophenol
A mixture of trans-6-styrI-2-nitrophenol (200 mg, 0.83 mmol) and un (II) chloride
(560 mg. 2.60 mmol) in cthanoI(50mL) was heated at 80°C under argon. After 2 hours, the
starting material has disappeared and the solution was allowed to cool down and then poured
into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH, before being
extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO, and
filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel
(4*8 McOH/ CH,CI,) gave the desired product (50 mg. 29 'H NMR (CD.OD): 5 7.5 1 (m.
3H>. 7.29 <m. 3H).7. 1 I (i. IH). 7.00 (m. 2H). 6.69 (m. 2H).
c Preparation of N-|lrans-3-siyrl-2-hydroxyphcnyl]-N'-[2-bromophenyI | urea
N-|iran.s-3-.styrl-2-hydmxy P henyl]-NW2-bromophenyl| urea was prepared from trans-
6-siyrl-2-aminophcnol (35mg. 0. 1 7 mmol) according in the procedure in General Method B.
The product was purified by precipitation from methylene chloride/ hcxane( 1/20) and filicrim-
<3ftmg. ). ' H NMR (CD.OD): 57.97 (d. IH). 7.62-7.48 (m. 4H). 7.45-7.26 ,m. 5H)/
7.2.5 it. IH). 7.15 (d. IH). 7.01 (t. IH). 6.88 (t 2H).
Example 120
Preparation ol " N-l2-hvdroxv-3.4-dirhlnrnph e n vll-N l -l"'-m^.hoxvph < >nvl | urr»
N'-|2-hydrox>-3.4-d.chlorophenyl|-N'-[2-mcihoxyphenyl] urea was prepared from 2-
ammo-5.6-dichlorophenol (XOmg. 0.50 mmol. example 82b) according to the procedure in
General Method B. The product was purified by precipitation from methylene chloride/
hcxane( 1/20) and filtering. ( 125mg.779f ). 'H NMR (CD,OD): 5 8.02 (d. IH). 7.79 (d. IH).
7.05-6.86 tm. 4H). 3.92 (s. 3H).
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Example 121
Preparation of N-12-hydroxy-3.4-dichlorophenvll-N'-[4-methoxvphenvll urea
N-f2-hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl| urea was prepared from 2-
amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to ihe procedure in
General Method B. The product was purified by precipitation from methylene chloride/
hcxane(lequiv./2()equiv.) and filtering. (12()mg, 74%). 'H NMR (CDiOD): 5 7.89 (d. 1H).
7.35 (d. 2H), 6.99 (d, 1H), 6.90 (dd, 2H), 3.80 is, 3H).
Example 122
Preparation of N-12-hvdroxv-3.4-dichlorophenvll-N , -[3-trifluoromeihvl phenvll urea
N-[2-hydroxy-3,4-dichlorophenyl]-N'-[3-trifluorornethylphenyl] urea was prepared
from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the
procedure in General Method B. The product was purified by precipitation from methylene
chloride/ hexane(lequiv./20equiv.) and filtering. (130mg, 11%). l H NMR (CD^OD): 8 7.96
(d, 2H). 7.60 (d, 1H), 7.48 (t, 1H), 7.30 (d, 1H), 7.00 (d, 1H).
Example 12?
Preparation of N-[2-hvdroxv-3.4-dichlorophenv]l-N'-12-phenvlphenvll urea
N-[2-hydroxy-3.4-dichlorophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-
amino-5.6-dichlorophenol (80mg. 0.50 mmol. example 82b) according to the procedure in
General Method B. The product was purified by precipitation from methylene chloride/
hcxane(lequiv./20equiv.) and filtering. (1 lOmg. 5990. 'H NMR (CD,OD): 6 7.77 (d. 1H).
7 7? id. 1H), 7.53-7.14 (m. 8H). 6.95 (d. 1H).
Example 124
Preparation of N-[2-hvdroxv-3.4-dichloronhcnvl)-N'-[2.3-diehlorophcnvll urea
N-|2-Hydroxy-3.4-dichlorophenyl)-N'-[2.3-dichlorophenyl) urea was prepared from
2-amino-5.6-dichlorophenol (8()mg. 0.50 mmol. example 82b) according to the procedure in
Genera] Method B. The product was purified by precipitation from methylene chloride/
hcxane(lcquiv./2()equiv.) and filtering. ( 1 3()mg. 7 1 9, ). 'H NMR (CDiOD): 5 8.06 (dd. 1H).
7 91 td. 1H). 7.25 (m. 2H>. 7.00 (d. 1H).
Example 125
Preparation of N-12-hvdroxv-4-isopropvlphenvll-N'-[3-trifluoromcthylphcnv]l urea
a)Preparation of 2-nitro-5-isopropylphenol
3-isopropylphenol (3.0()g. 22 mmol) was dissolved in methylene chlonde(4()ml)
followed by the addition of sodium nitrate (2.06g. 24mmol). The addition of sulfuric acid
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(25ml7 3M) is then made, followed by addition of a catalytic amount of sodium nunte The
mixture was allowed to stir. After 24 h, the reaction mixture is diluted with methylene chloride
and extracted with water. The organic layer is dried over MgSO, and filtered. The solvent was
evaporated and chromatography of the resulting solid on silica gel (4%MeOH/ CH-.CN) gave
the desired product( 1.09g, 27 %). «H NMR (CD3COCD,): 8 7.95 (d.lH), 7.62 ("d.lH). 7 I I
(d, 1H), 2.95 (m, 1H), 1.24 (d, 6H).
b) Preparation of 2-amino-5-isopropylphenol
To a solution of 2-nitro-5-isopropylphenol(lg. 6.4 mmol) in mcthanol(5() mL) was
added 10% Pd/C (100 mg). The mixture was Hushed with argon, then hydrogen was bubbled
through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon
pressure overnight. The mixture was filtered through celite and the celite was washed with
methanol. The solvent was evaporated and chromatography of the resulting solid on silica ec l
(5%MeOH/ CH 2 C1 2 ) gave the desired product(775 mg, 93 9? ). *H NMR (CD.OD): 6 6.71-
6.44 (m, 3H). 2.73 (m, 1H). 1.20 (d, 6H).
c) Preparation of N-[2-hydroxy-4-isopropylphenyl]-N , -[3-trinuoromcthylphenylj urea
N-[2-hydroxy-4-isopropylphenyl]-N-[3-trinuoromethylphenyl] urea was prepared
from 2-amino-5-isopropylphenol (75mg. 0.50 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./2()equiv.) and filtering. (140mg. 83%). 'h NMR (CD,OD): 8 7.91 (d. 2H)
7.62 (d. 1H). 7.47 (t, 1H), 7.39 (d, 1H). 6.75 (s. 1H). 6.72 (d, 1H). 2.80 (m. IH) 1 -1 (d
6H).
Examnln l?<S
Preparation of N-[2-hv(1n)xv-3.n a nh l hvll-lM-. n .3-dirhlnrn P ^n Y » | ,.»>- f ,
N-|2-hydrox y -3-naphthyl]-N'-|2.3-dichlorophenyl] urea was prepared from 3-am.m.
2-naphthol ( 1 60mg. 1 .00 mmol) according to the procedure in General Method B The
product was purified by precipitation from methylene chloride/ hcxanc( lequiv /2()cuu>v » and
filtering. (285mg. 82* ). 'H NMR (CD,OD): 8 8.48 (s. lH).8.IO<d. IH).7.6K(d. I H
7.57 (d. 1H). 7.40-7.23 (m. 4H), 7.18 (d. 1H).
Example 177
Preparation of NJ 2-[f2,3-Dichlor othicn-S - v ) i l s ulfonvlam.nnlphcnvl l-N"-P-hmmonhmvl ■■„
a)Preparation of |2-K2.3-Dichlorothien-5-yl)|sullonylaminoanilinc|
The title compound was prepared according to General Method C usinc 2.3-
dichlorothiophcnc-5-suilonyl chloride (( 1 cq). The product was purified by Hash
chromatography on silica gel (ethyl acetatc/hexanc 2()/80-methylenc chloridcrmethano! 9< )/!()»
(1.25 g. 39 <7r). EI-MS m/z 321 (M-H)
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b)Preparalion of N-|2-((2.3-Dichloromicn-5-yl)]sulfonylamino|phenyl |-N'-(2-
bromophenyDurea
The tille compound was prepared from [2-[(2.3-dichlorothicn-5-
yl)]sulfonylaminoaniline (1.25 g,3.9 mmol) and 2-(bromophcnyl)isocyanatc (768 mg, 3.9
mmol) according to General Method B. The product was purified by Hash chromatography on
silica gel (ethyl acctaterhexane 30/70) (272 mg. 13 %) EI-MS m/z 520 (M-HV
Example 128
Preparation of N-f 2-l(3.5-Bistrifluoromethylphenyl)sulfonvlaminolphenvl l-N'-(2-
10 hromophenvDurea
a) Preparalion of [2-(3,5-Bistrilluoromethylphenyl)sulfonylaminoaniline|
The title compound was prepared according to General Method C using 3,5-
(bistrifluoromethyl)phenylsulfonyl chloride (1.28 g, 4.1 mmol) and o-phenylenediamine (441
mg, 4. 1 mmol). The product was purified by flash chromatography on silica gel (methylene
15 chloride:methanol 95/5) (61 1 mg, 39 %). EI-MS m/z 383 (M-H)
b) Preparation of N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino|phenyl]-N'-(2-
bromophenyDurea
The tille compound was prepared from [2-(3,5-bisirifluoromeihylphenyl)
sulfonylaminoaniline (591 mg, 1.5 mmol) and 2-bromophenylisocyanatc (305 mg. 1.5 mmol)
20 according to General Method B. The product was purified by Hash chromatography on silica
gel (ethyl acetate: hexane 30/70) (10 mg. 1 %). EI-MS m/z 580 (M-H)
Example 129
Preparation of N-12-l(2-Benzvl).sulfonvlaminol-(5-trifluoronKnhvl )phcnvl l-N'-(2-
hromophenvDurea
a) Preparation of |(4-Benzylsulfonylamino)-(3 -nitro)-bcnzoinl"luonde |
4-Amino-3-nilro-bcnzotrinuoridc ( 1 .0 g. 4.85 mmol i was mixed m DMF and the
reaction mixture was cooled lo 0"C. Sodium hydnde (175 mg. 7. 28 mmol ) was added io the
cold mixture and allowed to mix lor icn minutes ( a deep red color was noted).
Toluencsulfonyl chloride (925 mg. 4.85 mmol) was added i reaction color changed to yellow t
and the reaction was mixed for sixteen hours at room temperature. The reaction was quenched
in NHjCl and extracted with ethyl acetatc:hexanc ( 1:1). The product was purified by Hash
chromatography on silica gel ( ethyl acetaic:hexanc 30/70) (878 mg. 52 '/'< ) EI-MS m/z 359 (M-
H) .
b) Preparation of [(4-Bcnzylsulfonylamino)-(3-amino)-benzotri fluoride |
[(4-Benzylsulfonylamino)-(3-mtro)-benzotrifluoride (230 mg. 0 64 mmol) was mixed
in methanol and poured into a Parr bottle. Palladium on carbon (15 mg) was added under an
argon stream. The reaction mixture was placed on a Parr shaker ( 55 psi. H 2 ) for several
30
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hours. The reaction mixture was tillered through Celitc to give the title compound (2 10 m«
99%) EI-MS m/z 329 (M-H) .
OPrcparauon of N-f2-[(2-Bcn/yl)sul(onylamino|-(5-trinuoromcihyl)pheny]|-N'-(2-
bromophenyl)urea
The title compound was prepared from |(4-benzylsulfonylamino)-(3-amino)-
benzotrilluonde (210 mg, 0.64 mmol) and 2-bromophcnylisocyanate f 126 mg. 0.64 mmol)
according to the procedure in General Method B. The product was purified by flash
chromatography on silica gel (ethyl acetate: hexanc 30/70) (70 mg, 21*) EI-MS m/z 526 (M
H)
Example 130
Preparation ot•N.r^f2-fVN^^^^)Dhenvl)slllfonv]aminolph e nvll-N^.^■h^omonh^»nvnll^ Pa
a)Preparation of [2-((3-Nitrophenyl)sulfonylamino)aniline]
The title compound was prepared according to General Method C using 3-
nitrobenzenesulfonyl chloride (I eq). The product was purified by flash chromatogrphy on
silica gel (methylene chloride:methanol 96/4).(l.()7 g, 37 %) EI-MS m/z 294 (M+H) +
^Preparation of N-[2-[(3-Niirophcnyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
The title compound was prepared from [2-(3-nitrophenyl)sulfonylaminoanilinc] (590
mg, 2.0 mmol) and 2-(bromophenyl)isocyanaie (398 mg. 2.0 mmol) according to the
procedure in General Method B. The product was punficd by flash chromatography on silica
gel (ethyl acelaterhexanc 30/70) (400 mg. 40%). EI-MS m/z 489 (M-H)
Example 131
Preparation ol N-[2-[g-(4-Phcnoxvphenvl)siilfonvh l mmol p h cnvl l-K'-f ?-hr„monhrnvl > urea
a) Prcparaiion of 12-((4-Phcnoxyphcnyl)sulibnylamino)anilinc|
The title compound was prepared according to General Method C using 4-
phcnoxyphcnylsulfonyl chloride (969 mg, 3.6 mmol) and o-phcnylenediaminc (300 mg. 2.77
mmol). The reaction mixture was partitioned between water (200 ml) and toluencrmethylcne
chloride ( 1 :3). The organic phase collected and the methylene chloride evaporated leaving the
toluene. Hcxane added and the product precipatated from solution. (317 mg. 34 % ) EI-MS
m/z 341 (M+Hf
b) Preparation ot N-|2-[(4-Phcnoxyphenyl ).sulfonylamino|phcnyl |-N , -(2-bromophenyl )tirea
The title compound was prepared from [2-(4-phcnoxyphenyi)sullonyl
aminoanihne (276 mg. 0.8 mmol) and 2-(bromophcnyl)isocyanate ( 161 mg. 0.8 mmol)
according to the proccdurcd in General Method B. The product was purified by Hash
chromatography on silica gel (ethyl acetatc:hexane 30/70) (240 mg. 55 %) EI-MS m/z 536 (M-
, ... .....
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Example 132
Preparation of N-fI2-( 1 S)- 10-Camphorsulfonylaminolphenyll-N'-(2-hromophenvl)urea
a) Prcparauon of 2-((lS)-l()-Camphorsulfonylamino)aniline
5 The liile compound was prepared according to General Method C using (lS)(+)-10-
Camphorsulfonyl chloride f 1.16 g, 4.6 mmol) and o-phenylenediaminc (500 mg. 4.6 mmol).
The reaction mixture was partitioned between water (200 ml) and toluenc:methylcnc chloride
(1:3). The organic phase was separated and the methylene chloride evaporated leaving the
toluene. Hexanc was added and solid precipitated from solution. (130 mg. 9%) EI-MS m/z
10 323 (M+H)'
b) Preparalion of N-[|2-( lS)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
The title compound was prepared from [2-(lS)-l()-camphorsulfonylamino]aniline (130
mg. 0.4 mmol) and 2-(bromophenyl)isocyanate (80 mg. 0.4 mmol) according to the procedure
in General Method B. The solvent was evaporated and product was precipitated from
15 methylene chlonde:hexane. (200 mg. 95 %). EI-MS m/z 518 (M-HV
Example 133
Preparation of N-H2-( IR)- 10-Camphorsulfonvlaminolphenvll-N'-(2-hromophcnvl)urea
a) Prcparalion of 2-(( 1R)- IO-Camphorsulfonylamino)aniline
20 The title compound was prepared according to General Method C using ( 1 R)(-)- 1 0-
camphorsulfonyl chloride ( 1. 16 g. 4.6 mmol) and o-phenylenediaminc (500 mg. 4.6 mmol).
The reaction mixture was partitioned between water (2(K) mL) and toluenc:mcihylene
chloridci 1 :3). The organic phase was separated and the methylene chloride evaporated leaving
the toluene Hexanc was added and the product precipitated from solution (563 mg. 38 c /f )
25 EI-MS m/z 323 (M+H)*
b) Preparation of N-||2-( I R)- 10-Camphorsulfonylaminolphenyl]-N'-(2-bromophcnyl (urea
The title compound was prepared from [ l-( 1R)- 10-camphorsulfonylaminoaniline| (563
mil. 1.75 mmol) and 2-(bromophenyl)isocyanaie (346 mg. 1.75 mmol) according to the
procedure in General Method B. The product was purified by Hash chromatography on silica
30 gel (ethyl aectate:hexane 30/70) (263 mg. 29 c 7< ) EI-MS m/z 5 1 8 (M-H)
Example 134
Preparation of N-l2-l2-(2-Nitrt)-(4-trintu)n)mcthyl)phenyl)sulfonylaminolphenyl-N"-(2-
bromophenvDurca
35 a (Preparation of |2-|(2-Nilro)-i4-tnnuoromcthyl)phenyl)sulfonylamino]anihne
The title compound was prepared according to General Method C using 2-nitro-4-
UrilluoromethyDbenzenesulfonyl chloride (1 eq). The product was purified by Hash
chromatography on silica gel » methylene chloridc:mcihanol 96/4) (875 mg. 25 c 7< ) EI-MS
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m/z 362 (M+H) +
b)_Prcparation of N-|2-|2-(2-Nilro-(4-irinuoromethyl)phenyl)sulfonylamin()|pheny]-N'-(2-
bromophcnyDurea
The title compound was prepared from [2-[(2-nitro)-(4-trilluoromethyl)
5 phenyl jsulfonylamino (aniline (740 mg, 2. 1 mmol) and 2-(bromophenyl)isocyanate (406 mg.
2. 1 mmol) according to General Method B. The product was purified by Hash
chromatography on silica gel (ethyl acetate rhcxane 30/70). The product was further purified by
recrystallization in ethyl acetate:hexane. (320 mg, 28 %) EI-MS m/z 557 (M-H)"
Example 135
H) Preparation of N-(2-hvdroxv-4-azidophenvl)-N'-(2-iodophenvl)urea
a) Preparation of N-(2-hydroxy-4-aminophenyl)-N'-(2-iodophenyl)urea
To a solution of N-(2-hydroxy-4-nitrophenyl)-N'-(2-iodophenyl)urea (220 mg, 0.55
mmol) in eihanol (15 mL), Tin chloride (522 mg, 2.75 mmol) was added. The reaction mixture
was surred at reflux for 16 hours then cooled to room temperature. The reaction mixture was
1 5 basified to pH 8 with aq. NaHCO, then extracted with ethyl acetate (3x). The organic extracts
were combined, dried over MgS0 4 , filtered and concentrated under reduced pressure to give
product (180 mg, 89%). EI-MS m/z 370 (M+H)*
b) Preparation of N-(2-hydroxy-4-azidophenyl)-N'-(2-iodophenyI)urea
The N-(2-hydroxy-4-aminophenyl)-N'-(2-iodophenyl)urea(77 mg. 0.21 mmol) was
20 added to HC1/H 2 0 (0.2 1 mL/0.42 mL), and cooled to 0°C. Sodium nitrate ( 1 4.5 mg. 0.2 1
mmol) was added to the reaction mixture. The reaction mixture was stirred at 0°C for 30
minutes. Sodium azidc ( 14 mg, 0.2 1 mmol) was added to reaction mixture and it was warmed
to room temperature. The reaction mixture was stirred at room temperature for 18 hours. Then
li was extracted with three times by ethyl acetate. The organic extracts were combined, dried
25 over MgS0 4 . filtered and concentrated under reduced pressure and chromatography of the
resulting solid on silica gel (hcxanc : ethyl acetate: 5:1) gave product (20 mg. 24<# ). EI-MS m//
396 <M+H)V
Example 136
30 Preparation of N-(2-hydroxv-3-azidophcnyl)-N'-(2-hromophenvl)urea
a) Preparation of N-(2-hydroxv-3-aminophcnyl )-N'-(2-bromophcnyl)urca
To a solution of N-(2-hydroxy-3-nilrophcny!)-N'-(2-bromophcn\i lurea (300 mg. O.S>
mmol) in eihanol (20 mL). Tin chloride (958 mg. 4.25 mmol) was added. The reaction mixture
w as stirred at reflux lor 16 hours then cooled to room temperature. The reaction mixture was
35 basified to pH 8 with aq. NaHCOi then extracted with ethyl acetate (3x). The organic extracLs
were combined, dried over MgS0 4 . filtered and concentrated under reduced pressure to give
product (274 mg. 99%). EI-MS m/z 323 (M+HV.
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h) Preparation of N(2-hydroxy-3-azidophenyl)-N'-(2-bromophenyl)urca
The N-(2-hydroxy-3-aminophcnyl)-N-(2-bromophenyl)urea(274 mg. 0.85 mmol) wa>
added lo HC1/H 2 0 (0.85 mL/1.7 mL). cooled to 0°C. Sodium nitrate (58.6 mg. 0.85 mmol)
was added lo the reaction mixture. The reaction mixture was stirred at O 'C lor 30 minutes.
5 Sodium azide (55 mg, 0.85 mmol) was added to reaction mixture and it was warmed to room
temperature. The reaction mixture was stirred at room temperature for 18 hours then it was
extracted with three limes with ethyl acetate. The organic extracts were combined, dried over
MgS0 4 , filtered and concentrated under reduced pressure and chromatography of the resulting
solid on silica gel (hexane : ethyl acetate: 5: 1 ) gave product (2 10 mg. 7 1 <%■). EI-MS m/z 349
10 (M+H)-.
Example 137
Preparation of N-r2-hvdroxv-3-cvanonhen vll-N , -[2-methoxvnhenvll nrr.a
N-[2-hydroxy-3-cyanophenyl]-N'-f2-methoxyphenyl] urea was prepared from 2-
15 amino-6-cyanophenol (134mg, 1.00 mmol) according to the procedure in General Method B
The product was purified by precipitation from methylene chloride/ hcxane(lequiv./2()cquiv.)
and filtering. (230 mg, 81%). 'H NMR (CD 3 OD): 5 8.06 (d. 1H). 7.79 (d. IH), 7.49-7.35
(m. 2H), 7.05-6,87 (m. 3H), 3.95 (s, 3H).
2<> Example 138
Preparation of N-r2-hvdroxv-3-cvanophp.n vll-N , -f3-trifluoromelhvlnhenvll urea
N-[2-hydroxy-3-cyanophenyl)-N , -|3-irifluoromethylphcnyl] urea was prepared from
2-amino-6-cyanophcnol (134mg, 1.00 mmol. example 83a) according to the procedure in
General Method B. The product was purified by precipitation from methylene chloride/
25 hcxane(lequiv./20equiv.) and filtering. (280mg. 87<7r ). ! H NMR (CDiOD): 5 8. 10 (d. 1H>.
7.96 (s. 1H). 7.54 (d. 1H). 7.55-7.25 (m. 3H). 7.01 (i. 1H).
Example 139
Preparation of N-l2-hvdroxv-3-cvanophenvll-N"-l2-phenvlphcnvll urea
3 (> N-[2-hydroxy-3-cyanophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-ammo
6-cyanophcnol ( I34mg. 1.00 mmol. example 83a) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexanc(lequiv./20equiv.) and filtering. (270mg, 82<5? ). 'H NMR (CD,OD): 8 7.81 id. IHi.
7.75 (d. 1H). 7.56-7.15 (m. 9H). 6.91 (i. IH).
Example 140
Preparation of N , -f2-hvdroxv-3-cvanophenvll-N'-r2.3-dichlorophenvll urea
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N-[2-hydroxy-3-cyanophenyl|-N , -[2.3 dichlorophcnyl| urea was prepared from 2-
amino-6-cyanophenol (134mg, l.(K) mmol. example 83a) according to the procedure in
General Method B. The product was purified by precipitation from methylene chloride/
hcxane(lequiv./20equiv.) and filtering. (3(>0mg. 93 6 7r). ! H NMR (CD,OD): 8 8. 1 1 (d. 1H).
5 8 01 (d, IH). 7.33-7.25 (m, 3H), 7.00 (t, 1H).
Example 141
Preparation of N-[2-hvdroxv-4-i.';opronvlphftnvll -N , -12.3-dichloronhenvl I nrr;i N-|2-
hydroxy-4-isopropylphenyl]-N'-[2,3-dichlorophenylj urea was prepared from 2-amino-5-
10 isopropylphenol (150 mg, 1.00 mmol, example 128a) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering (285mg, 84%). l H NMR (CD,OD): 5 8.05 (d. 2H).
7.77 (s, 1H). 7.26 (m, 2H), 6.88 (m. 2H), 2.82 (m. 1H). 1.25 (d. 6H).
15 Example 142
Preparation of N-f2-hvdroxv-4-isonronvlnh envll-N , -f2-chloro-5-trinuoromethvlphenvll urea
N-[2-hydroxy-4-isopropylphenyll-N'-[2-chloro-5-lrinuoromclhylphenyll urea was
prepared from 2-amino-5-isopropylphenol (150mg, 1.00 mmol. example 128a) according to
the procedure in General Method B. The product was purified by precipitation from methylene
20 chloride/ hexane( lequiv./20equiv.) and filtering. (275mg. 827, ). 'H NMR (CD^OD): 5 8.50
(s. 1H). 7.70 (s. 1H). 7.51 (d. 1H). 7.22 (d. 1H). 6.70 (m. 2H). 6.62 (dd. IH). 2.76 (m.
(1H). 1.16 (d. 6H).
Example 143
2S Preparation of N^2-hvdroxv-3-nhp nvlnhcnvll-NM2.3-dichloronricnvl I urea
a)Prcparation of 2-nitro-6-phcnylphenoI
2-phenylphenol (3.00g. 17.6mmoI) was dissolved in methylene chloride(40ml i
followed by the addition of sodium nitrate (1.65g. 194mmol> The addition of sulfuric acid
(25ml/ 3M) was then made, followed by addition ol a catalytic amount oj sodium nitrite The
30 mixture was allowed to stir. After 24 hrs. the reaction mixture was diluted with methylene
chloride and extracted with water. The organic layer was dried ov er MgS0 4 and filtered. The
solvent was evaporated and chromatography of the resulting solid on silica gel (49; MeOH/
CH 2 C1 2 ) gave the desired product(900 mg. 24 9, ). 'h NMR <CD3COCDo: 5 X. 19 <d. I Hi.
7.79 (d.lH). 7.64 (d. 2H). 7.50 (I. 2H). 7.45 (t. IH). 7.22 it. IH)
35 b)Preparalion of 2-amino-6-phenylphenol
To a solution of 2-nitro-6-phenylphenol(9()() mg. 4.2mmol> in mcthanolr.SOml) was
added 10 f 7r Pd/C (100 mg). The mixture was Hushed with argon, then hydrogen was bubbled
through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon
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pressure overnight. The mixture was filtered through cclitc and the eclite was washed with
methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel
(5%MeOH/ CH 2 C1 2 ) gave the desired product(700 mg. 90 <7< ). 'H NMR (CD1OD): 8 7.55-
7.27 (m, 5H), 6.77-6.6 1 (m, 3H)
5 c)Preparation of N-[2-hydroxy-3-phcnylphcnyl|-N'-[2,3-dichloropheny]] urea
N-[2-hydroxy-3-phenylphenyl)-N'-[2.3-dichlorophenyl| urea was prepared from 2-
amino-6-phenylphenol (92.5mg, 0.50 mmol) according to the procedure in General Method B.
The product was purified by precipitation from methylene chloride/ hcxanc( lequiv./20cquiv.)
and filtenng. ( I50mg,8 \ c 7< ). 'H NMR (CD-,OD): 8 8.06 (d. 1H).7.65 (d. IH). 7.54 (d,
l() 2H),7.40 (l. 2H), 7.32 (d, IH) 7.22 (m, 2H), 7.04-6.88
Preparation of N-[2-hydroxy-3-phenylphenyl]-N'-[2.3-dichlorophenyI) urea
b)N-[2-hydroxy-3-phenylphenyl)-N , -I2,3-dichlorophenyl] urea was prepared from 2- amino-
6-phenylphenol (92.5mg, 0.50 mmol) according to the procedure in General Method B. The
product was purified by precipitation from methylene chloride/ hexane( lequiv./20equiv.) and
15 filtering. (150 mg, 81%). 'H NMR (CD ? OD): 8 8.06 (d, IH),7.65 (d. IH). 7.54 (d,
2H).7.4() (t, 2H), 7.32 (d, IH) 7.22 (m. 2H), 7.04-6.88 (m. 2H).
Example 144
Preparation of N -[2-hvdroxv-5-nitrophp.nvll-N l -r2-methoxvphpnvl 1 ut^ -a
20 N-[2-hydroxy-5-nitropheny])-N'-[2-methoxyphenyl] urea was prepared from 2-amino-
4-nitrophenol (154 mg, 1.00 mmol) according to the procedure in General Method B. The
product was purified by precipitation from methylene chloride/ hcxane( lequiv./2()equiv.) and
filtering. (270 mg. 899? ). ! H NMR (CD ? OD): 8 9.10 (s. lH).8.10(d. IH). 7.85 (d. IH).
7.08-6.88 (m. 4H). 3.96 (s. 3H)
25
Example 145
Preparation of N-[2-hvdrox\ -5-nitror)hcnvll-N'-f 3-trinuoromethvlphenvll urea
N-[2-hydroxy-5-nitrophcnyl|-N'-[3-lrinuoromelhylphenyl] urea was prepared Irom 2-
amino-4-mtrophenol (154 mg. 1.00 mmol) according to the procedure in General Method B
30 The product was purified by precipitation from methylene chloride/ hcxanc( lequiv ./20eqmv. )
and filtering. (290 mg. 859? ). 'H NMR (CDiOD): 8 9.12 (s. IH). 7.89 (d. I H). 7.68 (d.
IH). 7.55 <m. 2H). 7.45 (d. IH). 7 ()() (d. IH).
Example 146
35 Preparation of N-[2-hvdroxv-5-nurophenvll-N'-l2-phenylphcnvll urea
N-|2-hydroxy-5-mirophcnyIl-N , '-[2-phenylphcnyl| urea was prepared from 2-aminn-4-
nitrophenol ( 154 mg. 1.00 mmol) according to the procedure in General Method B The
product was purified by precipitation irom methylene chloride/ hexanef lequiv./20cquivj and
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filiering. (285 mg.8I<*). ! H NMR (CD,OD): 5 8.09 (s. 1 H), 7.86 (d. 1 H) 7 58-7 20 (m
9H). 6.95 (d. 1H).
Example [4J
Preparation of N-f2-hv(1roxy-5-pi|rn phpnvH - N '- f? .3-dirhlnmp h . n Yn „ r n
N-|2-hydroxy-5-nnrophcnyIl-N--[2.3-dichlorophenyl] urea was prepared from
am.no-4-muophenoI (154 mg, 1.00 mmol) according to the procedure in General Method B
The product was purified by precipitation from methylene chloride/ hexane( lequiv /20euu.v )
andfiltcnng. (290 mg, 85*). 'H NMR (CD^OD): 5 9. 1 1 (s, 1H), 8.17 (d, IH) 7 89 (d
1H), 7.34 (m. 2H). 6.95 (d. 1H).
Example 14S
Preparanon of N-r?-hv<lmxy-'S-rThYls ulfnnvlnhrnvn -N--r? ^.hi^ p^,,., ^
N-f2-hydroxy-5-ethylsullonylphenyl]-N'-[2.3-d,chlorophenylJ urea was prepared from
2-amino-4-(ethylsulfonyl)pheno] (185 mg. 1.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hcxane(lequiv./20cquiv.) and filtering. (3I0mg.84%). »H NMR (CD,OD): 5 8 65 (s IH)
8.18 (d. IH). 7.45 (d, IH), 7.26 (m, 2H). 7.00 (d. IH), 3.33 (q, 2H). 1.24 (t. 3H).
The following compounds of Formula (I) may be prepared in accordance with the examples
and schemes as described above:
Example 149 : N-[2-(2-Am 1 no-(4-trifiuoromethyl) phenyl) sulfonylamino) phenyl]- N-(2-
bromophenyDurca EI-MS m/z 527 (M-H)
Example 150 : N-|2-(ammosullonyl phenyl) 3-amino phenyll N'-(2-bromo phenyl , urcaEl-MS
m/z 426 (M+HV.
The following compounds of Formula (I) may be prepared in accordance with the
examples and schemes as described above, or may also be purchased commercially from well
recognized sources. For instance, from Aldrich Chemical Company:
N-(2-Hydroxy-4-nitrophcnyl)-N-phenylurca
For instance, from the Alfred Badcr Collection of Aldrich Chemical:
l-(2-Carboxyphcnyl)-3-(3-nuorophcnyl)urca
l-(2-Carboxyphenyl)-3-(3-chlorophcnyl)urca
Available from Gallard Schlcsingcr Company and/or the Sigma Aldrich Library of Rare
Compounds:
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l-(2-Carboxyphenyl)-3-(4-ch]orophenyl)urca
1- (p-Anisyl)-3-(2-carboxyphcnyl)urea
Available from Gallard Schlisingcr Company :
2- (3.4-Dichlorophenylcarbonyldiimino)-5-trilluoromclhylbenzoic acid
2-(4-Chlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid
N-Phenyl-N'-(2-carboxyphenyl)urea
From Maybridge Chemical Company, Cambridge England:
1 . 1 '-(4-Methyl-2-phenylene)bis[3-tolyl)]thiourea
N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N'-phenylurea
The following compounds of Formula (I) may be prepared in accordance with the examples
and schemes as described above, or as indicated by their respective citations in Chemical
Abstracts:
l-(m-Anisyl)-3-(2-carboxyphneyl)urea;
1 -(o-Anisyl)-3-(2-carboxyphenyl)urea ;
l-(2-CarboxyphenyI)-3-(3.4-dichlorophenyl)urea:
l-(2-Carboxyphenyl)-3-(2,4-dichlorophenyl)urea;
METHOD OF TREATMENT
The compounds of Formula (I), (la), (II) and (III), or a pharmaceutically acceptable salt
thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic
treatment of any disease slate in a human, or other mammal, which is exacerbated or caused by
excessive or unregulated IL-8 cytokine production by such mammal's cell, such as but nol
limited to monocytes and/or macrophages, or other chemokines which bind to the IL-8 a or P
receptor, also referred to as the type I or type II receptor.
For purposes herein, the compounds of Formula (I), (la). (Ib). (Ic). (II) and (III) all
have the same dosages, and dosage formulations as that of Formula (I) are used
interchangeably.
Accordingly, the present invention provides a method of treating a chemokine mediated
disease, wherein the chemokine is one which binds to an IL-8 a or p receptor and which
method comprises administering an effective amount of a compound of Formula (I) or a
pharmaceutical^ acceptable salt thereof. In particular, the chemokines ais IL-S. GROa.
GROp. GROy or NAP-2.
The compounds of Formula (1) arc administered in an amount sufficient to inhibit
cytokine function, in particular IL-8.GROa. GROp. GROyor NAP-2 . such that they are
biologically regulated down to normal levels of physiological function, or in some case to
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subnormal levels, so as to ameliorate the disease state. Abnormal levels of IL-8. GROa.
GROp, GROyor NAP-2 for instance in the context of the present invention, constitute: (i)
levels of free IL-8 greater than or equal to 1 picogram per mL: (u) any cell associated IL-8.
GROa, GROp, GROyor NAP-2 above normal physiological levels: or (iii)the presence of IL
8, GROa, GROP. GROyor NAP-2 above basal levels in cells or tissues in which IL-8,
GROa, GROp. GROyor NAP-2respectively, is produced.
There are many disease states in which excessive or unregulated IL-8 production is
implicated in exacerbating and/or causing the disease. Chemokine mediated diseases include
psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult
respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis
stroke, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac
and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs. host reaction,
alzheimers disease, allograft rejections, malaria, restenosis, angiogenesis or undesired
hematopoietic stem cells release.
These diseases are primarily characterized by massive neutrophil infiltration, T-ccll
infiltration, or neovascular growth, and are associated with increased IL-8, GROa, GROp.
GROyor NAP-2 production which is responsible for the chemotaxis of neutrophils into the
inflammatory site or the directional growth of endothelial cells. In contrast to other
inflammatory cytokines (IL-1, TNF. and IL-6), IL-8. GROa. GROp. GROyor NAP-2 has
the unique property of promoting neutrophil chemotaxis. enzyme release including but noi
limited to elastase release as well as superoxide production and activation The a-chemokmes
but particularly. GROa. GROp. GROy or NAP-2. working through the IL-8 type 1 or U
receptor can promote the neovascularization of tumors by promoting the directional growth ol
endothelial cells. Therefore, the inhibition of IL-8 induced chemotaxis or activation would lead
to a direct reduction in the neutrophil infiltration.
The compounds of Formula (I) are administered in an amount sufficient to inhibit IL-S.
binding to the IL-8 alpha or beta receptors, from binding to these receptors, such as evidenced
by a reduction in neutrophil chemotaxis and activation. The discovery that the compounds m
Formula (I) are inhibitors of IL-8 binding is based upon the effects of the compounds ol
Formulas (I) in the //; vitro receptor binding assays which are described herein. The
compounds of Formula (I) have been shown to be dual inhibitors of both recombinant type 1
and type II IL-8 receptors. Preferably the compounds are inhibitors of only one receptor,
preferably Type II
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As used herein, the term "IL-8 mediated disease or disease state" refers to anv and all
disease states in which IL-8. GROa. GROp, GROy or NAP-2 plays a role, cither by
production of IL-8, GROa, GROp. GROy or NAP-2 themselves, or by IL-8. GROa, GROp.
GROy or NAP-2 causing another monokine to be released, such as but not limited to IL- 1 . IL-
6 or TNF. A disease state in which, for instance, IL- 1 is a major component, and whose
production or action, is exacerbated or secreted in response to IL-8. would therefore be
considered a disease stated mediated by IL-8.
As used herein, the term "chemokine mediated disease or disease state" refers to any
and all disease states in which a chemokine which binds to an IL-8 a or P receptor plays a role,
such as but not limited to IL-8, GRO-a, GRO-P, GRO-y, or NAP-2. This would include a
disease state in which, IL-8 plays a role, either by production of IL-8 itself, or by IL-8 causing
another monokine to be released, such as but not limited to IL- 1 , IL-6 or TNF. A disease state
in which, for instance, IL-1 is a major component, and whose production or action, is
exacerbated or secreted in response to IL-8, would therefore be considered a disease stated
mediated by IL-8.
As used herein, the term "cytokine" refers to any secreted polypeptide that affects the
functions of cells and is a molecule which modulates interactions between cells in the immune,
inflammatory or hematopoietic response. A cytokine includes, but is not limited to. monokines
and lymphokines, regardless of which cells produce them. For instance, a monokine is
generally referred to as being produced and secreted by a mononuclear cell, such as a
macrophage and/or monocyte. Many other cells however also produce monokines, such as
natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone
marrow stromal cells, epideral keratinocytes and B-lymphocytcs. Lymphokines are generally
referred to as being produced by lymphocyte cells. Examples of cytokines include, bin are iu>i
limited to, Intcrleukin- 1 (IL-1). Intcrlcukin-6 (IL-6), Inlcrleukin-8 (IL-8), Tumor Necrosis
Factor-alpha (TNF-a) and Tumor Necrosis Factor beta (TNF-B).
As used herein, the term "chemokine" refers to any secreted polypeptide thai aflects the
functions of cells and is a molecule which modulates interactions between cells in the immune,
inflammatory or hematopoietic response, similar to the term "cytokine" above. A chemokine is
primarily secreted through cell transmembranes and causes chemotaxis and activation ot
specific white blood cells and leukocytes, neutrophils, monocytes, macrophages. T-cells. B-
cells. endothelial cells and smooth muscle cells. Examples of chemokines include, bin are noi
limited to. IL-8. GRO-a, GRO-p. GRO-y. NAP-2. IP- 10. MlP-la. MIP-p. PF4. and MCP
1. 2. and 3
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In order to use a compound of Formula (I) or a pharmaceutical ly acceptable salt thcreol
in therapy, it will normally be formulated into a pharmaceutical composition in accordance with
standard pharmaceutical practice. This invention, therefore, also relates to a pharmaceutical
composition comprising an effective, non-toxic amount of a compound of Formula (I) and a
5 pharmaceulically acceptable carrier or diluent.
Compounds of Formula (I), pharmaceulically acceptable salts thereof and
pharmaceutical compositions incorporating such may conveniently be administered by any of
the routes conventionally used for drug administration, for instance, orally, topically,
10 parenterally or by inhalation. The compounds of Formula (I) may be administered in
conventional dosage forms prepared by combining a compound of Formula (I) with standard
pharmaceutical carriers according to conventional procedures. The compounds of Formula (I)
may also be administered in conventional dosages in combination with a known, second
therapeutically active compound. These procedures may involve mixing, granulating and
15 compressing or dissolving the ingredients as appropriate to the desired preparation. It will be
appreciated that the form and character of the pharmaceulically acceptable character or diluent is
dictated by the amount of active ingredient with which it is to be combined, the route of
administration and other well-known variables. The camcris) must be "acceptable" in the
sense of being compatible with the other ingredients of the formulation and not deleterious to
20 the recipient thereof.
The pharmaceutical carrier employed may be. lor example, either a solid or liquid.
Exemplary of solid carriers arc lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia,
magnesium stearate. stearic acid and the like. Exemplary ol liquid carriers are syrup, peanut
25 oil. olive oil, water and the like. Similarly, the carrier or diluent may include time delay
material well known to the art. such as glyceryl mono-sicaraie or glyceryl disiearate alone or
with a wax.
A wide variety of pharmaceutical forms can he employed. Thus, il a solid carrier is
30 used, the preparation can be lablctcd. placed in a hard gelatin capsule in powder or pellet form
or in the form of a troche or lozenge. The amount of solid carrier will vary widely but
preferably will be from about 25mg. to about lg. When a liquid earner is used, the preparation
will be in the form of a syrup, emulsion, soft gelatin capsule, sterile iniectable liquid such a.s an
ampule or nonaqueous liquid suspension.
35
Compounds of Formula (I) may be administered topically, that is by non-systemic
administration. This includes the application of a compound of Formula (I) externally to the
epidermis or the buccal cavity and the instillation ol such a compound into the ear. eye and
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nose, such that the compound docs not significantly enter the blood stream. In contrast,
systemic administration refers 10 oral, intravenous, intraperitoneal and intramuscular
administration.
5 Formulations suitable for topical administration include liquid or semi-liquid
preparations suitable for penetration through the skin to the site of inflammation such as
liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the
eye. car or nose. The active ingredient may comprise, for topical administration, from 0.001%
to 10% w/w, for instance from \9< to 29c by weight of the Formulation. It may however
10 comprise as much as I0 6 7< w/w but preferably will comprise less than 59c w/w. more
preferably from 0. 1 9c to 1 9c w/w of the Formulation.
Lotions according to the present mvenuon include those suitable for application to the
skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a
1 5 bactericide and may be prepared by methods similar to those for the preparation of drops.
Lotions or liniments for application to the skin may also include an agent to hasten drying and
to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil
such as castor oil or arachis oil.
20 Creams, ointments or pastes according to the present invention arc semi-solid
formulations of the active ingredient for external application. They may be made by mixing the
active ingredient in finely-divided or powdered form, alone or in solution or suspension in an
aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy
base The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol.
25 beeswax, a metallic soap: a mucilage: an oil o! natural origin such as almond, corn, arachis.
castor or olive oil: wool fat or its derivatives or a fatly acid such as stene or oleic acid together
with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any
suitable surface active agent such as an anionic, canonic or non-ionic surfactant such as a
sorbnan ester or a polyoxycihylcnc derivative thereof. Suspending agents such as natural
30 gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other
ingredients such as lanolin, may also be included.
Drops according to the present invention may comprise sterile aqueous or oils solutions
or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous
35 solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and
preferably including a surface active agent. The resulting solution may then be clarified by
filtration, transferred to a suitable container which is then sealed and sterilized bv autoclaving
or maintaining at 98- 1(X)°C. for half an hour. Alternatively, the solution may be sterilized by
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filtration and transferred to the container by an aseptic technique. Examples of bactericidal and
fungicidal agents suitable for inclusion in the drops are phcnylmercuric nitrate or acetate
(0.002*), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable
solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene
glycol.
Compounds of formula (I) may be administered parenterals, that is by intravenous,
intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal
administration. The subcutaneous and intramuscular forms of parenteral administration are
generally preferred. Appropriate dosage forms for such administration may be prepared by
conventional techniques. Compounds of Formula (I) may also be administered by inhalation,
that is by intranasal and oral inhalation administration. Appropriate dosage forms for such
administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by
conventional techniques.
For all methods of use disclosed herein for the compounds of Formula (I), the daily
oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body
weight. The daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body
weight. The daily topical dosage regimen will preferably be from 0. 1 me to 150 mg,
administered one to lour, preferably two or three times daily. The daily inhalation dosage
regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day. It will also be
recognized by one of skill in the art that the optimal quantity and spacing of individual dosages
of a compound of Formula (I) or a pharmaceutical^ acceptable salt thereof will be determined
by the nature and extent of the condition being treated, the form, route and site of
administration, and the particular patient being treated, and that such optimums can be
determined by conventional techniques. It will also be appreciated by one of skill in the art thai
the optimal course of treatment, i.e.. the number of doses of a compound of Formula (I ) or a
pharmaceuticals acceptable salt thereof given per day for a defined number of days, can be
ascertained by those skilled in the art using conventional course of treatment determination
tests.
The invention will now be described by reference to the following biological examples
which arc merely illustrative and arc not to be construed a.s a limitation of ihe scope of the
present invention
BIOLOGICAL EXAMPLES
The IL-S. and Gro-a chemokine inhibitiory effects of compounds of the present
invention were determined by the following in vitro assay:
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Receptor Binding Assays:
[ 125 I] IL-8 (human recombinant) was obtained from Amersham Corp., Arlington
Heights, IL, with specific activity 2(KX) Ci/mmol. Gro-a was obtained from NEN- New
England Nuclear. All other chemicals were of analytical grade. High levels of recombinant
human IL-8 type a and 0 receptors were individually expressed in Chinese hamster ovary cells
as described previously (Holmes, etal.. Science, 1991, 253, 1278). The Chinese hamster
ovary membranes were homogenized according to a previously described protocol fHaour. e,
al.,JBiol Chem., 249 pp 2195-2205 (1974)). Except that the homogcnization buffer was
changed to 10mM Tris-HCL, ImM MgS()4, 0.5mM EDTA (ethyiene-d.aminetetra-acetic acid).
ImMPMSF (a-toluenesulphonyl fluoride), 0.5 mg/L Leupeptin. pH 7.5. Membrane protein
concentration was determined using Pierce Co. micro-assay kit using bovine serum albumin as
a standard. All assays were performed in a 96-well micro plate format. Each reaction mixture
contained ^1 IL-8 (0.25 nM) or ^ Gro . a and 0 5 ^ g/mL of IL 8Ra or l 0 ^ g/mL Qf JL
8RP membranes in 20 mM Bis-Trispropane and 0.4 mM Tris HC1 buffers, pH 8.0. containing
1 .2 mM MgS0 4 , 0. 1 mM EDTA, 25 mM NaCl and 0.03% CHAPS. In addition, drug or
compound of interest was added which had been pre-dissolved in DMSO so as to reach a final
concentration of between O.OlnM and 100 uM. The assay was initiated by addition of l2 5l-
IL-8. After 1 hour at room temperature the plate was harvested using a Tomtec 96-well
harvester onto a glass fiber filtermat blocked with 1% polyethylenimine/0.5% BSA and washed
3 times with 25 mM NaCl. 10 mM TrisHCl. 1 mM MgS04, 0.5 mM EDTA. 0.03 % CHAPS.
pH 7.4. The filter was then dried and counted on the Betaplate liquid scintillation counter. The
recombinant IL-8 Ret, or Type I. receptor is also referred to herein as the non-permissive
receptor and the recombinant IL-8 Rf3. or Type II. receptor is referred to as the permissive
receptor.
All of the exemplified compounds of Formulas (I) to (III ) noted herein in the Synthetic
Chemistry Section, of Examples 1 to 150 plus the additional purchased compounds
demonstrated an IC50 from about 45 to about <1 u.g/mL in the permissive models lor IL-8
receptor inhibition. All of these compounds were also found to be inhibitors of Gro-a bindin-
at about the same level. The compound I -(2-Carboxyphenyl)-3-(4-chloro-2-
methvlphenvDurca was found to be active at about 75 ug/mL.
The following compounds, generally tested at levels of up to 45 ug/mL were found to
not demonstrate levels of IL-8 receptor antagonism within the criteria set forth above at the
dosage levels tested. These compounds arc:
l-(4-Chloro-alpha.alpha,alpha-trifluoro-3-tolyl)-3-[2-(4-chlorophenyl)thio]-5-
chlorophenyl urea
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l-(6-Chloro-alpha,alpha,alpha-trifluoro-3-tolyl)-3-[2-(4-chlorophenoxy)-5-
chlorophenyljurea
l-(2-Mercaptophenyl)-3-phenyl-2-thiourea
l-(2-Hydroxyphenyl)-3-phenyl-2-thiourea
5 3,3'-(Carbonothioyldiimino)bis[4-hydroxybenzoic acid]
m,m'-(l ,3-thioureylene)diC4-hydroxybenzoic acid)
l-(2-TolyI)-3-(3-chloro-6-hydroxyphenyl)-2-thiourea
l-[(2-Hydroxy-4-aminophenyI)]-(3-phenyl)-urea
N-(2-Carboxy-4-trinuromethylphenyl)-N'-(3-chlorophenyl)urea
1 0 N-(2-Carboxyphenyl)-N'-(2,5-dichlorophenyl)urea
1- (2-Carboxyphenyl)-3-(2-Chloro-5-trifluoromethylphenyl)urea
2- [2-[3-(4-Bromophenyl)ureido]-4-trifluoromethylphenoxy]benzoic acid;
2-[2-[3-(4-Chlorophenyl)ureido]phenoxy]benozic acid
2-[2-[3-(4-Chloro3-(trifluromethyl)phenyl)ureido]phenoxy]benozic acid
15 N- (2-Hydroxyphenyl) -N'-phenyl urea
N-[2-Hydroxy-5-(methoxycarbonyl)phenyl]-N'-phenylurea
N-[4-Carboxy-2-hydroxyphenyl]-n'-phenylurea
N-(2-Hydroxy-4-nitrophenyl)-N'-C4-nitrophenyI)urea;
l-(2-Carboxyphenyl)-3-(2,6-xylyl)urea
20 l-(6-Carboxy-2.4-dich]orophenyl)-3-(2,4 t 6-trichlorophenyl)urea
l-(2-Carboxyphenyl)-3-(2,5-dimethoxyphenyl)urea
l-(2-Carboxyphenyl)-3-(2-methylphenyI)urea
l-[(2-Hydroxyphenyl)-3-(2-methyl)-5-nitrophenyl]urea
l-(2,5-Dichlorophenyl)-3-(2-hydroxy-4-nitrophenyl)urea
25 l-(2-Carboxyphenyl)-3-(4-chloro-2-methylphenyl)urea
N-(2-phenylsulfonylaminophenyl-N'-phenylurea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-ethoxycarbonylphcnyl)urca
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-eihoxycarbonylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-ethoxycarbonylphenyl)urca
30 N-(2-Hydroxy-4-nitrophenyI)-N'-(4-phenylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-phenoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-propylphenyl)urea
N-(4-Trinuromethyl-2-(4-nitrobenzenesulfonyl)amino]-N'-phenylurca
N-(3-Carboxyphenyl)-N , -2-hydroxy-4-nitrophenyl)urea
35 N-{4-Trinuromethyl-2-(methylsulfonyl)amino]-N'-phenylurea
N-(2-Hydroxy-4-nitrophenyl)-N'-f2-(isopropyl)phenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-dimethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nuoro-5-nitrophenyl)urea
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N-(2-Hydroxy-4-nitrophenyl)-N'-(2-chloro-5-trifluromcthylphcny] (urea
N-(2-Hydroxy-4-nitrophenyl)-N'-r2-mcthoxy-4-nitn)phcnyl)urca
N-(2-Hydroxy- l-napthyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-5-ethylsulfonylphenyl )-N'-(2-bromophenyl )urca
5 N-(2-hydroxy 3,4 dichlorophenyl )-N'-(4-phenyiphenyl)urca
N-(2- hydroxy -3-naphthyl)-N'-(2-meihoxyphenyl)urea
N-(2-hydroxy-3-naphtbyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-3-naphthyl)-N'-(4-methoxyphenyl)urea
N-(2-Hydroxy-3-naphthyl)-N'-(3-trinuoromethylphenyl)urea
10 N-(2-Hydroxy-3-naphthyl)-N'-(4-phenylphenyl)urea
N-[2-(2-CarboxyphenylsuHonylamino)phenylJ-N'-(2-bmmophcnyl)urca
N-(2-Hydroxy-3-phenylphenyl)-N'-(2-melhoxyphenyl)urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(4-methoxyphenyl)urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(3-triflouromethylphenyl)urca
1 5 N-(2-Hydroxy-3-phenylphenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(4-phenylphenyl)urea
N-f2-[(2,5-Dichlorothien3-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urca
N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2,4 dimeihoxyphenyl)urea
N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-chloro-5-trifloromethylphcnynurea
20 N-(2-Hydroxy-3-naphthyl)-N'-(2.4 dimethoxyphenyl)urea
N-(2-Hydroxy-3-naphthyl)-N'-(2-chloro-5-trinuoromethylphenyl)urca
N-(2-Hydroxy-3 phcnylphenyl)-N'-(2.4-dimethoxyphcnyl)urca
N-(2-Hydroxy-4-isopropylphcnyl)-N'-(2,4-dimethoxyphcnyl )urca
N-(2-Hydroxy-3-phcnylphenyl)-N'-(2-chloro-5-trifluoromcthyl phenyl )urcii
25 N-(2-Hydroxy-5-nitrophenyl)-N'-(2.4-dimeihoxyphenyl)urca
N-(2-Hydroxy-5-nitrophenyl)-N'-(2-chloro-5-lrinu()romLHhylphcnyl JurtM
N-(2-Hydruxy-3-cyanophenyl)-N'-(4-mcthoxyphcnyl)urca
N-(2-Hydroxy-3-cyanophenyl)-N'-(4-phcnylphenyl)urca
N-(2-Hydroxy-3-cyanophenyI)-N'-(2.4 dimclhoxyphcnyl mrca
30 N-(2-Hydroxy-3-cyanophenyl)-N'-(2-chlon)-5-lriniK>n)nicihyl phenyl )urca
N-(2-Hydroxy- 5-phenylphenyl)-N'-(2-meihoxyphenyl)urca
N-(2-Hydroxy- 5-phenylphenyl )-N-(4-melhoxyphcnyl)urca
N-(2-Hydroxv- 5-phenylphenyl )-N'^ 3-trifluoromeihyl phenyl )urca
N-(2-Hydroxv- 5-phcny]phenyl)-N'-(2-phenylphcny! )urca
35 N-(2-Hydroxy-5-phenylphenyl)-N'-(4-phenylphenyI)urea
N-(2-Hydroxy-5-phenylphenyl)-N'-(2.3-dichlorophenyl)urca
N-(2-Hydroxy-5-phenylphenyr>-N'-(2.4-dimelhoxyphcnyr)urca
N-(2-Hvdroxv-5-phcnylphenyl)-N'-(2-chloro-5-lrinuaromethyl phenyl lure a
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N-a-Hydroxy-5-cthyl.suironylphcnyI)-N'-(4-mcihoxyphenyl)urca
N-(2-Hydroxy-5-eihyl.suironylphcnyl)-N'-(3-trini.or()mcihylphcnyl)urca
N-f2-Hydroxy-5-ethyIsullonylpheny])-N , -(2-phcny]phcny])urca
N-(2-Hydroxy-5-ethylsuilony]pheny])-N'-(4-phenylphcnyl)urea
N-C2-Hydroxy-5-eihyJsullonylphenyl)-N , -(2,4-dimeihoxyphenyl)urea
N-(2-Hydroxy-5-ethylsullonylphenyl)-N-(2-chlor()-5.irin U (,romeihy]phenyl)urea
N-f2-Hydn)xy-3.4-dichJorophcnyI|-N , -f2,4d,melhoxyphcny]| urea
N-(2-Hydroxy-3.4-dichloro P hen y l]-N--f2-chloro-5-trinuoromcthyl P henyl]urca
N-f2-Hydroxy-3-naphlhyl|-N -[3-lrinuoromethylphenyl| urea
Chemot axis Assay ;
The in vitro inhibitory properties of these compounds were determined in the
neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol I. Suppl
1 . Unit 6. 1 2.3.. whose disclosure is incorporated herein by reference in its entirety.
Neutrophils where isolated from human blood as described in Current Protocols in
Immunology Vol I. Suppl 1 Unit 7.23. 1, whose disclosure is incorporated herein by
reference in its entirety. The chemoattraciants IL-8. GRO-a. GRO-f3. GRO-yand NAP-2
where placed in the bottom chamber of a 48 muliiwell chamber (Neuro Probe. Cabin John
MD) at a concentration between 0. 1 and 100 nM. The two chambers where separated by a
5um polycarbonate filter. When compounds of th.s invention were tested, thev where mixed
with the cells (0.001 - 1 (MX) nM) just prior to the addition of the cells to the upper chamber.
Incubation was allowed to proceed for between about 45 and 90 min at about 3 7 <> C in a
humidified incubator with 5* CO, At the end of the incubat.on period, the polycarbonate
membrane was removed and the top side washed, the membrane was then stained using the
Dill Quick staining protocol (Baxter Products. McGaw Park. IL. USA). Cell which had
chemotaxed to the chcmokinc were visually counted usmg a microscope. Generally four
fields where counted for each sample, these number where avcraccd to snve the average
number of cells which had migrated. Each sample was tested in triplicate and each compound
repeated at least four times To certain cells (pos.nve control cells) no compound was added,
these cells represent the maximum chcmoiaciic response of the cells In the case where a
negative control (unstimulated) was desired, no chcmokinc was added lo the boilom chamber
The difference between the positive control and the negative control represents the chemotacuc
activiiv of the cells.
Elasiase Release Assay:
The compounds of this invention where tested tor their ability 10 prevent Elasta.se
release from human neutrophils. Neutrophils where isolated from human blood as described in
Current Protocols in Immunology Vol I. Suppl 1 Unit 7.23. 1 . PMNs O SS x 10^ cells
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suspended in Ringer's Solution (NaCl 1 18. KC1 4.56, NaHC03 25. KH2P04 1.03. Glucose
11.1. HEPES 5 mM, pH 7.4) where placed in each well of a 96 well plate in a volume of 50
ul To this plate was added the test compound (0.001 - 1000 nM) in a volume of 50 ul,
Cytochalasin B in a volume of 50 ul (20ug/ml) and Ringers buffer in a volume of 50 ul.
These cells where allowed to warm (37 °C, 5% C02, 95% RH) for 5 min before IL-8,
GROa. GROP. GROyor NAP-2 at a final concentration of 0.01 - 1000 nM was added. The
reaction was allowed to proceed for 45 min before the 96 well plate was ccntriluged (800 xg 5
min) and 1(X) ul of the supernatant removed. This suppernatant was added to a second 96 well
plate followed by an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC. Nova
Biochcm. La Jolla. CA) to a final concentration of 6 ug/ml dissolved in phosphate buffered
saline. Immediately, the plate was placed in a fluorescent 96 well plate reader (Cytofluor 2350.
Millipore. Bedford. MA) and data collected at 3 min intervals according to the method of
Nakajima et al J. Biol Chem 254 4027 (1979). The amount of Elastase released from the
PMNs was calculated by measuring the rate of MeOSuc-Ala-Ala-Pro-Val-AMC degradation
The above description fully discloses the invention including preferred embodiments
thereof. Modifications and improvements of the embodiments specifically disclosed herein are
within the scope of the following claims. Without further elaboration, it is believed that one
skilled in the are can, using the preceding description, utilize the present invention to its fullest
extent. Therefore the Examples herein arc to be construed as merely illustrative and not a
limitation of the scope of the present invention in any way The embodiments of the invention
in which an exclusive property or privilege is claimed arc defined as follows.
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1 A method of treating a chemokinc mediated disease state, wherein the chemokine binds
to an IL-8 a or (3 receptor in a mammal, which comprises administering to said mammal an
effective amount of a compound of the formula:
5
wherein
X is oxygen or sulfur;
R is any functional moiety having an lonizable hydrogen and a pKa of 10 or less:
10 R\ is independendy selected from hydrogen; halogen; nitro: cyano: halosubstitutcd C |. io
alkyl; Ci-io alkyl; C2-10 alkenyl: Ci-|() alkoxy: halosubstituted C|_io alkoxy; azidc:
S(0) t R4: hydroxy; hydroxy Ci-4alkyl; aryl; aryl C1.4 alkyl: aryloxy: aryl C1-4 alkyloxy:
heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Ci-4alkyl: heicroaryl C1.4 alkyloxy:
aryl C2- 10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic. 10 alkenyl: NR4R5; C2-I0
15 alkenyl C(0)NR4R 5 ; C(0)NR4R 5 ; C(O)NR4Ri 0 ; S(0)3H; S(0) 3 R 8 : C M( ) alkyl
C(0)R 1 1: C2-10 alkenyl C(0)R 1 1 ; C2- 1 () alkenyl C(0)OR 1 j ; C(0)R j \ ; C(0)OR 1 2:
OC(O) Ri 1 : NR4C(0)R 1 j: or two R 1 moieties together may form 0-(CH2) s O- or a 5 to 6
membered unsaturated ring;
1 is 0. or an integer having a value of 1 or 2:
20 s is an integer having a value of 1 to 3:
R4 and R5 are independently hydrogen, optionally substituted C1.4 alkyl. optionally
substituted aryl, optionally substituted aryl C1.4alk.vl. optionally substituted heteroaryl.
optionally substituted heteroaryl C)-4a)kyI, heterocyclic, heterocyclic C | .4 alkyl. or R4
and R5 together with the nitrogen to which they arc attached form a 5 to 7 member nnu
25 which may optionally comprise an additional hctcroaiom selected Irom O/N/S:
Y is independently selected from hydrogen: halogen: nitro: cyano: halosubstituted C\. 10 alkyl:
C 1 . ] 0 alkyl: C2- 10 alkenyl: C ] . 10 alkoxy: halosubstituted C 1 - 1 0 alkoxy: a/ide: Sc ( )),R4:
hydroxy: hydroxyC | -4alkyl: aryl: aryl C 1.4 alkyl: aryloxy: arylCj.4 alkyloxy: heieroaryl:
heteroarylalkyl: hetcroarylC 1 .4 alkyloxy: heterocyclic. heterocyclic |-4alkyl: arvl C'2- 10
30 alkenyl: heteroaryl C2- 10 alkenyl: hcierocyclicC2- 1() alkenyl: NR4R5: C2- 10 alkenyl
C(0)NR4R5:C(0)NR4R5: C(0)NR 4 Ri(): S(0)3H: S(0) 3 R X : Cj. | () alkyl C(0)R 1 | :
C2- 10 alkenyl C(0)R 1 ]: Cj- 10 alkenyl C(0)OR 1 1 ; CfO)R] |: C(0)ORi2: OOOt R| |:
NR4C(0)R 1 1 : or two Y moieties together may form 0-(CH2) s O- or a 5 to 6 membered
unsaturated ring:
35 n is an integer having a value of 1 to 3:
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m is an integer having a value of I lo 3;
R# is hydrogen or C | -4 alkyl:
Rl<)isCi-malkylC(0)2R8:
R| t is hydrogen, C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl C]-4alkyl,
5 optionally substituted heteroaryl, optionally substituted heteroaryl C | -4alkyl, optionally
substituted heterocyclic, or optionally substituted heterocyclic C i-4alkyl:
Rl2 is hydrogen, Ci-i() alkyl. optionally substituted aryl or optionally substituted arylalkyl:
or a pharmaceutically acceptably salt thereof.
10 2. The method according lo Claim 1 wherein the lonizable hydrogen has a pKa of 3 to 10.
3. The method according to Claim 2 wherein R is hydroxy, carboxylic acid, thiol. -SR2
-OR2, -NH-C(0)R a , -C(0)NR6R7. -NHS(0)2Rb- -S(0)2NHR C , NHC(X)NHR h . or
tetrazolyl;
1 5 wherein R2 is a substituted aryl, heteroaryl. or heterocyclic moiety which ring has the
functional moiety providing the ionizable hydrogen having a pKa of 10 or less:
R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring may
optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen
20 or sulfur;
R a is an alkyl, aryl. aryl Ci-4alkyl, heteroaryl. heteroaryl C|-4alkyl, heterocyclic, or a
heterocyclic C]-4alkyl moiety, all of which may be optionally substituted;
Rb us a NR6R7. alkyl. aryl. arylC 1 -4alkyl. arylC2-4alkcnyl. heteroaryl.
hcteroarylCi-4alkyl, heieroarylC2-4 alkcnyl. heterocyclic, heterocyclic C j_4alkyl. heterocyclic
25 C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three times
independently by halogen: nitro: halosubsiilutcd C1-4 alkyl: C|-4 alkyl: C|-4 alkoxy:
NRoC(0)R a :C(0)NR6R7. S(0)3H. or C(0)OC | .4 alkyl:
Ro is hydrogen or a C |-4 alkyl;
R c is alkyl, aryl. arylC | -4alkyl. arylC2-4alkcnyl. heteroaryl. hctcroarylC |-4alkyl.
30 hcteroarylC2-4alkenyl. heterocyclic, heterocyclic C 1 -4alkyl. or a heterocyclic C2-4alkcnvl
moiety, all of which may be optionally substituted one to three limes independent)) by halogen,
nitro. halosubstituted Ci-4 alkyl. C | -4 alkyl. Ci-4 alkoxy. NRoC(C))R a . C(GMNR6R7.
S(0)3H. 0i C(O)OC|-4 alkyl
35 4. The method according 10 Claim 3 wherein the R2 is optionally substituted one to three
limes by halogen, nitro. halosubstituted C i- 10 alkyl. C ] . 10 alkyl. C 1 - ] 0 alkoxy. hydroxy.
SH. -C(0)NR6R7. -NH-C(0)R a . -NHS(0)Rb. S(0)NRfiR7. C(0)ORs. or a tetrazolyl ring
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5. The method according to Claim 3 wherein R is OH. -NHS(0)2Rb or C(0)OH.
6 The method according to Claim I wherein R \ is halogen, cyano. nuro, CF3,
C(0)NR 4 R 5 , alkenyl C(0)NR 4 R5, C(O) R4R10. alkenyl C(0)ORi 2 , hetcroaryl,
hetcroarylalkyl . hcteroaryl alkenyl, or S(0)NR4R5.
7 The method according 10 Claim 1 wherein Y is halogen, C1-4 alkoxy, optionally
substituted aryl. optionally substituted arylalkoxy. methylene dioxy. NR4R5. thioCi- 4 alkyl,
thioaryl, halosubstitutcd alkoxy, optionally substituted Ci_ 4 alkyl, hydroxy alkyl.
8. The method according to Claim 1 wherein R is OH, SH, or NHS(0) s Rb and R | is
substituted in the 3-position. the 4- position or di substituted in the 3,4- position by an electron
withdrawing moiety.
9 The compound according to Claims 1 or 8 wherein Y is mono-substituted in the 2'-
position or 3'- position, or is disubsiituted in the T- or 3'- position of a monocyclic ring.
1 0. The compound according to Claims 1 , 8 or 9 wherein n amd m are each equal to 1 or
more.
11. The method according to Claim 1 wherein R is a carboxylic acid, and R ] is hydrogen,
or R] is substituted in the 4-position.
12 The method according 10 Claim 1 wherein the mammal is afflicted with a chemokme
mediated disease selected from psoriasis, or atopic dermatitis, asthma, chronic obstructive
pulmonary disease, adull respiratory distress syndrome, arthritis, inflammatory bowel disease.
Crohn's d.seasc. ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic-
shock syndrome, stroke, cardiac and renal rcperfusion injury, glomcmlo-nephritis. or
thrombosis, alzhcimers disease, graft vs. host reaction, or allograft rejections.
1 3 The method according to Claim 1 wherein the compound, or a pharmaceuticals
accepatable salt is:
N-f2-Hydroxy-4-niirophenyl)-N'-(2-mcthoxyphenyl)urca
.\'-(2-Hydroxy-4-niii()phenyl)-N'-(2-bromophenyl)urca
N-(2-Hydroxy-4-nilrophenyl)-N'-(2-phenylphenyl)urca
N-f2-Hydroxy-4-nitrophenyl)-N T '-(2-mcthylthiophcnyl)urca
N-(2-Hydroxy-4-niirophcnyl)-N , -f2.3-dichlorophcnyl)urea
N-(2-Hydroxy 4-nitro phenyl) N -(2-chloro phenyl) urea
wo
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N-(2-Hydroxy-4-nilrophcnyl)-N'-(2.3-methylcncdioxyphenyl)urca
N-(2-Hydroxy-4-nitrophcnyl)-N'-(2-mcihoxy-3-chlorophenyl)urea
N-(2-hydroxy 4-nitro phenyl) N'-(2-phenyloxy phenyl) urea
N-(3-Chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea
5 N-(2-Hydroxy-3-glycincmethylestercarbonylpheny])-N'-(2-bromophcnyl)urea
N-(3-Nitro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2-bromophenyl)urea
N-(3-Cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
10 N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydorxy-4-cyanophenyl-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methylphenyl)urea
N-(2-Hydroxy-3-cyano-4-methylphenyl)-N'-(2-bromophenyl)urea
1 5 N-(4-Cyano-2-hydroxyphenyl)-N'-(2-trifluoromethylphenyl)urea
N-(3-Trifluoromethyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(3-Phenylaminocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea
N-(2-hydroxy 4-niiro phenyl) N'-(2-iodo phenyl) urea
N-(2-hydroxy 4-niiro phenyl) N'(2-bromo phenyl) thiourea
20 N-(2-phenylsultonamido)-4-cyanophenyl-N'(2-bromo phenyl)urea
(E)-N-l3-[(2-Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-(2-bromophenyl)urea
N-f2-Hydroxy.3.4-dichlorophenyl)-N'-(2-meihoxyphcnyl)urea
N-( 2- Hydroxy. 3.4-dichlorophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-3.4-dichlorophenyl)-N'-(2.3-dichlorophenyl)urea
25 N-(2-Hydrox\ -5-nurophenyl)-N'-(2,3-dichlorophenyl)urea; or
N-(2-Hydrox> -3-cyanophenyl)-N'-(2.3 dichlorophcnyDurea.
14 A compound of ihc formula:
E is optionally selected from
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or
point of attachment of the ring; wherein at least one E ring is present:
or a pharmaceuiically acceptably salt thereof.
the asierix * denoting
15. A pharmaceutical composition comprising a compound according to Claim 14 and a
pharmaceuiically acceptable carrier or diluent.
16 A method of treating a chemokine mediated disease state, wherein the chemokine binds
to an IL-8 a or p receptor in a mammal, which comprises administering to said mammal an
effective amount of a compound of the formula according to Claim 14.
17.
A compound of the formula:
(Y)n
=(Ri)m
(ID
wherein
X is oxygen or sulfur:
R is any functional moiety having an lonizablc hydrogen and a pKa of !() or less:
R| is independently selected from hydrogen: halogen: nitro: cyano: halosubsthuted C\.\o
alkyl: C|.|()alkyl: C2- 10 alkenyl: C\. | ( ) alkoxy: halosubstiiuicd C ] . |(» alkoxy: azide:
S(0) t R4: hydroxy: hydroxyC | -4alkyl: aryl: aryl C|-4 alkyl: aryloxy: aryIC|-4 alkyloxv:
heteroaryl: heicroarylalkyl: heterocyclic, heterocyclic i-4alkyl: heteroarylC |. 4 alkyloxv:
aryl C2-K) alkenyl: heteroaryl C2- |o alkenyl: heterocyclicC2- 1() alkenyl: NR4R5: C2- 10
alkenyl C(0)NR 4 R5: C(0)NR 4 R 5 : C(0)NR 4 Rl(): S(0)3H: S(0)3Rs: C|.|o alkyl
C(0)R 1 1 : C2- 1 0 alkenyl C(0)R 1 1 : C2- 10 alkenyl C(0)OR 1 1 : C(0)R | 1 : C(0)OR 12:
OC(O) R I 1 : NR4C(0)R] ]: or two R | moieties together may form 0-(CH2)sO- or a S u, (,
mcmbcrcd unsaturated ring;
1 is 0. or an integer having a value of 1 or 2:
s is an integer having a value of I to 3:
R4 and R5 arc independently hydrogen, optionally substituted C 1 -4 alkyl. optionally
substituted aryl. optionally substituted aryl C 1 -4alkyl. optionally substituted hcicroaryl.
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optionally substituted heieroaryl C|-4alkyl, heterocyclic. heierocyclicCi-4 alkyl. or R4 and
R5 together with the nitrogen to which they are attached form a 5 10 7 member ring which
may optionally comprise an additional heteroatom selected from O/N/S;
Y is independently selected from hydrogen; halogen; nitro; cyano; halosubsthuted C 1. 10 alkyl:
5 C 1-10 alkyl; C2-I0 alkenyl; Ci- 10 alkoxy; halosubstituted Ci-K) alkoxy; azidc: S(0) t R4:
hydroxy; hydroxyCi-4aJkyl; aryl; aryl C)-4 alkyl; aryloxy; arylCi-4 alkyloxy: hctcroaryl:
heteroarylalkyl; heteroarylC 1 .4 alkyloxy; heterocyclic, heterocyclic i-4alkyl: aryl C2-10
alkenyl: heieroaryl C2- 10 alkenyl; heterocyclicC2- 10 alkenyl: NR4R5: C2- 10 alkenyl
C(0)NR4R5; C(0)NR4R5: C(0)NR4R K); S(0)3H: S(0)3Rg: C | - ] 0 alkyl C(0)R 1 1 :
10 C2- 10 alkenyl C(0)Ri 1 ; C2- 1 0 alkenyl C(0)OR 1 ] : C(0)Ri | : C(0)ORi2: OC(O) R| |;
NR4C(0)Ri ] ; or two Y moieties together may form 0-(CH2) s O- or a 5 to 6 mcmbcred
unsaturated ring;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3:
15 Rg is hydrogen or C 1-4 alkyl;
RlO is C 1-10 alkyl C(0)2R8;
Rl 1 is hydrogen, C 1-4 alkyl, optionally substituted aryl. optionally substituted aryl Ci-4alkyl.
optionally substituted heteroaryl, optionally substituted heteroarylC i-4alkyl, optionally
substituted heterocyclic, or optionally substituted heterocyclic i-4alkyl;
20 R12 is hydrogen, C l-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
or a pharmaceutical^ acceptable salt thereof.
18. A pharmaceutical composition comprising a compound according lo Claim 17 and a
pharmaceutical! y acceptable carrier or diluent.
25
19. A method of treating a chemokine mediated disease state, wherein the chcmokine binds
to an IL-8 a or (3 receptor in a mammal, which comprises administering 10 said mammal an
effective amount of a compound of the formula according to Claim 17
30 20. A compound of the formula:
NHS(0) 2 R b
wherein
X is oxygen or sulfur;
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R a is an alkyl, aryl, arylC|-4alkyl. hcicroaryl. heteroarylC|-4alkyl. heterocyclic, or a
heterocyclic Ci-4alkyl moiety, all of which may he optionally substituted:
Rb is a NR6R7. alkyl, aryl. arylC | -4alkyl. arylC2-4alkcnyl. heteroaryl. hctcroarylC 1 -4alkyl.
hetcroarylC2-4 alkenyl, heterocyclic, or heterocyclic C|-4alkyl. or a heterocyclic
C2-4alkenyl moiety, camphor, all of which may be optionally substituted one to three time
independently by halogen: nitro: halosubstituied C | .4 alkyl: C | .4 alkyl: C ] .4 alkoxy:
NR9C(0)R a ; C(0)NR 6 R7. S(0)3H. or C(0)OC 1 .4 alkyl;
R6 and R7 are independently hydrogen or a C 1.4 alkyl group, or R 6 and R 7 together with the
nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally
contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or
sulfur,, which ring may be optionally subsiitued;
R9 is hydrogen or a C 1-4 alkyl;
R| is independently selected from hydrogen: halogen: nitro: cyano: halosubstituied Ci- 10
alkyl: Ci-io alkyl: C2-10 alkenyl: C i- 10 alkoxy: halosubstituied C\. 10 alkoxy: azide:
S(0) t R4: hydroxy; hydroxyCi- 4 alkyl; aryl; aryl C1.4 alkyl: aryloxy: arylCi.4 alkyloxy:
heteroaryl: heteroarylalkyl; heterocyclic, heterocyclicCi-4alkyl: heteroarylC ] .4 alkyloxy;
aryl C2- 1 0 alkenyl; heteroaryl C2- 10 alkenyl; heterocydicC2- 10 alkenyl: NR4R5: C2-10
alkenyl C(0)NR4Rs: C(0)NR4R5: C(0)NR4Rio: S<0) 3 H: S(0)3Rs: C]. 10 alkyl
C(0)R 1 1: C2-IO alkenyl C(0)R 1 ] : C2- 1 0 alkenyl C(0)OR 1 1 : C(0)R 1 1 : C(0)OR 12:
OC(O) R 1 1 : NR4C(0)R ] 1 : or two R 1 moieties together may form 0-(CH2) s O- or a 5 to 6
membercd unsaturated ring;
t is 0. or an integer having a value of I or 2:
s is an integer having a value of 1 to 3:
R4 and R5 are independently hydrogen, optionally substituted C 1-4 alkyl. optionally
substituted aryl, optionally substituted aryl C 1 -4alkyl. optionally substituted hcicroaryl.
optionally substituted heteroaryl Ci.4alkyl, heterocyclic. hcicrocyclicC | -4 alkyl. or R4 and
R5 together with the nitrogen 10 which they arc attached form a 5 10 7 member ring which
may optionally comprise an additional heteroatom selected from O/N/S:
Y is independently selected from hydrogen: halogen: nitro: cyano: halosubstituied C \. 10 alkyl:
C1-10 alkyl: C2- 10 alkenyl: C|_ 10 alkoxy: halosubsii lined C ]. 10 alkoxy: a/.ide: S(0),R4:
hydroxy: hydroxyC] -4alkyl: aryl: aryl Ci-4 alkyl: aryloxy: arylC 1.4 alkyloxy: hcicroaryl:
heteroarylalkyl: heteroarylC | .4 alkyloxy: heterocyclic. hcicrocyclicC | -4alkvl: aryl C2-K)
alkenyl: heteroaryl C2-H) alkenyl: heterocyclic C2- 1() alkenyl: NR4R5: C/>- 10 alkenyl
C(0)NR 4 R5: C(0)NR4R5: C(0)NR 4 R|(): S(0)3H: S(0) 3 Rs: C 1 - 1 0 alkyl C(0)R| 1 :
C2- 1 () alkenyl C(0)R 1 | : C2- 1 0 alkenyl C(0)OR 1 ] : C(0)R 1 | ; C(0)OR 12: OC(O) R | 1 :
NR4CfO)R 1 1 ; or two Y moieties together may form 0-(CH2) s O- or a 5 to 6 membercd
unsaturated ring:
n is an integer having a value of 1 to 3:
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m is an integer having a value of I 10 3;
Rx is hydrogen or C ] -4 alkyl ;
RlO is C mo alky] C(0)2Rs:
R| 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl C]-4alkyl.
5 optionally substituted hetcroaryl, optionally substituted heteroaryl C |_4alkyl, optionally
substituted heterocyclic, or optionally substituted heterocyclic C ]-4alkyl:
R 12 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyh
or a pharmaceutically acceptably salt thereof.
10 21. The compound according to Claim 20 wherein R i is substituted in the 3-position, the
4- position or di substituted in the 3,4- position by an electron withdrawing moiety.
22. The compound according to Claim 20 or 2 1 wherein Y is mono-substituted in the 2'-
position or 3'- position, or is disubstituted in the 2 - or 3 - position of a monocyclic ring.
15
23. The compound according to Claim 20 or 2 1 wherein n amd m are each equal to 1 or
more.
24. The compound according to Claim 20 which is
20 N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phcnyl urea
N-l(2-Phenylsullamido) 4-cyanophenyl]- N'-(2-bromo phenyl) urea
N-(2-( Amino sulfonamido phenyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sullonyl styryl) phenyl) N'-(2-bromo phenyl) urea
2-|(3.4 Di-melhoxyphcnylsullonyl (amino | phenyl) N'-(2-bromo phenyl) urea
25 N-(2-((4-Acetamidophcnylsullonyl)amino) phenyl") N'-(2-bromo phenyl) urea
N-(2-( Amino sullonyl (2-thiophenc) phenyl) N"-(2-bromo phenyl) urea
N-(2-(Amino sullonyl (3-lolyl) phenyl) N'-(2-bromo phenyl) urea i
N'-(2-( Amino sullonyl (8-quinolinyl)) phenyl) N"-(2-bromo phenyl) urea
N-(2-(Amino sullonyl benzyl) phenyl) N'-(2-bromo phenyl) urea
30 N-| 2-[[|2-fTrinuoromcthyl)phcnyl]sulfonyl|amino|phenyl|-N'-(2-bromophcnyl)urea
N-(2-Bromophcnyl)-N'-|2-dimclhylaminosull"onylamino)phcnyl|urca
N-|2-(Phenethylsul!onylamino)phcnyl)-N'-(2-broni(iphenyl)urca
N-|2-|(2-Aceiamid()-4-melhylthia/^)l-5-yl)sullbnylaniino|phcnyl|-N'-(2-bn>mi)phcnyl)urea
N-| 2-((2.3-Dichlorolhien-5-yl)|sulfonylamino]phenyl]-N'-(2-bromophenyl)urca
35 N-|2-|(3.5-Bisirilluoromcthylphenyl)sull"onylamino|phenyl]-N'-(2-brt)mophcnyl)urea
N-|2-[(2-Benzyl)sullonylamino]-(5-trifluoromelhynphenyl]-N'-(2-bromophcnyl)urea
N-|2-[2-f3-Nitrophenyl)sulfonylamino]phenyll-N"-(2-bromophcnyr)urea
N-[2-|2-(4-Phenoxyphcnyl)sullonylamino]phenyl|-N'-(2-bromophenyl) urea
WO 96/25157
PCT/US96/02260
- 107 -
N-ll2-(lS)-l()-Camphorsulfonylamino]phcnyl|-N , -(2-bromophenyl)urca
N-||2-(IR)-l()-Camphor.sulfonylamino]pheny]]-N'-(2-bromophcnyl)urca
N-|2M2-(2-N.tro-<4- l rinuoromelhyl)phenyl)su]fonylaminoJphenyl-N'-(2-bromopheny]) U rca
N-f2-C2-Amino-(4-trinuoromethyl) phenyl) sullonylamino] phenyl]- N'-(2-
bromophenyDurea : or
N-[2-(aminosuifonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea.
27 A pharmaceutical composition comprising a compound according lo any of Claims 22
to 27 and a pharmaceutically acceptable carrier or diluent.
28. A compound of the formula:
H
wherein
X is oxygen or sulfur;
X i is oxygen or sulfur;
R| is independently selected from hydrogen; halogen: nitro; cyano: halosubstituted C M0
alkyl : C ] . |o alkyl: C 2 - 1 () alkenyl : C t . , 0 alkoxy : halosubstituted Cj-io alkoxy : azidc:
S(0) t R 4 : hydroxy; hydroxyC]. 4 alkyl: aryl; aryl Ci_ 4 alkyl: arvloxy; aryl C,. 4 alkyloxy
hcteroaryl: hcteroarylalkyl: heterocyclic. hclcrocyclicCi. 4 alkyl: hetcroarylC i- 4 alkyloxy:
aryl C 2 - ] () alkenyl: hcteroaryl C 2 - 1() alkenyl: heterocyclic C 2 - 1() alkenyl: NR4R 5 - O \ 0
alkenyl C(0)NR4R S : C(0)NR 4 R 5 ; C(O)NR 4 R 10 : S(0) 3 H: S(0) 3 R«: Cj. |() alkyl
C(0)R | | : C 2 - K) alkenyl C(0)R ] | : C 2 . io alkenyl C(0)OR j | : CfO)R | | : C(0)OR 1 2 :
000) R i | : NR 4 00)R j j ; or two R , moieties together may form CHCH 2 ) s O- or a 5 lo 6
mcmbcred unsaturated ring;
i is 0. or an integer having a value of 1 or 2:
s is an integer having a value of 1 to 3:
R 4 and R 5 arc independently hydrogen, optionally substituted Cj. 4 alkyl. optionally
substituted aryl. optionally substituted aryl C|. 4 alkyl. optionally substituted hetcroarvl.
optionally substituted hcteroaryl C | -4 alkyl. heterocyclic, heterocyclic Cj- 4 alkyl. or R 4
and R 5 together with the nitrogen to which they are attached form a 5 to 7 member ring
which may optionally comprise an additional hctcroatom selected from O/N/S:
Y is independently selected from halogen: nitro; cyano; halosubstituted C |. io alkyl: Cj. ] o
alkyl: C 2 -W alkenyl: Cj. ]() alkoxy: halosubstituted C M() alkoxy; azide: SfO) t R4:
hydroxy: hydroxy C !-4alkyl: aryl: aryl C , _ 4 alkyl: aryloxy; arylC , . 4 alkvloxv: hetcroarvl:
WO 96/25157
- 108 -
PCT/US96/02260
heieroarylalkyl: heteroarylC 1 -4 alkyloxy: heierocyclic. heterocyclic C]-4alkyl: aryl C2-K)
alkenyl: hctcroaryl C2-10 alkenyl: heterocyclic C2- 10 alkenyl: NR4R5: C2-K) alkenvl
C(0)NR4R5; C(0)NR4R5: C(0)NR4R 1(): S(0)3H; S(0)3R8: C 1 - 1 0 alkyl CfO)R | 1 :
C2- 1 0 alkenyl C(0)R 1 1 : C2- 1 0 alkenyl C(0)OR 1 1 ; C(0)R 1 1 : C(0)OR 1 2: OC(O) R ] | :
5 NR4C(0)R 1 1 : or two Y moieties together may form 0-(CH2).sO- or a 5 to 6 membered
unsaturated ring:
n is an integer having a value of 1 to 2;
m is an integer having a value of 1 to 3;
R8 is hydrogen or Ci-4 alkyl;
10 Rio is C 1-10 alkyl C(0)2R8;
R 1 1 is hydrogen, C1.4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl.
optionally substituted heteroaryl, optionally substituted heteroaryl C]-4alkyl, optionally
substituted heterocyclic, or optionally substituted heterocyclic C i_4alkyl;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl:
15 provided that:
when n =1 than Y is substituted in the 2 - or 3'- position;
when n =2 than Y is di-substituted in the 2'- 3'- position:
further provided that
when X| is S, m=l, R\ is 4-elhyl. and n=l than Y is not 2-methoxy:
20 or a pharmaceutical^ acceptably salt thereof.
27 The compound according to Claim 26 wherein R | is substituted in the 3-posiuon. the
4- position or di-substituted in the 3.4- position by an electron withdrawing moiety.
25 28. The compound according to Claim 26 or 27 wherein Y is mono-substituted in the 2 -
position or 3'- position, or is disubstituted in the 2' or 3' position of a monocyclic ring
29. The compound according to Claim 26 or 27 wherein n amd m arc each equal 10 I 01
more.
30
30. A pharmaceutical composition comprising a compound according to any of Claims 2^
to 29 and a pharmaceutical^ acceptable carrier or diluent.
31. A process for producing a cyano phenol derivative of the formula:
WO 96/25157
PCT/US96/02260
109
OH
R,
X
wherein R | is as defined for Formula (I) above, which method comprises
a) reacting a compound of the formula:
OH
R,
wherein X is halogen
with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount of
dimethylamino pyridine.
32. The process according to Claim 3 1 wherein the temperature is about 60 to about HO C.
and X is bromine.
10
WO 96/25157 ~" U PCT/US96/02260
AMENDED CLAIMS
[received by the International Bureau on 16 July 1996 (16.07.96);
original claims 1-32 replaced by amended claims 1-32 (3 pages)]
N-(2-Bromophenyl)-N'-[2-dimethylaminosulfonylamino]phenyl]urea
N-[2-(Phenemylsulfonylamino)phenyl]-N'-(2-bromophenyI)urea
N-[2-[(2-Acetamido-4-methyIthiazol-5-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[(2,3-DichIorothien-5-yl)]sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
5 N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl) urea
N-[[2-(lS)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
1 0 N-[[2-( 1 R)-10-Caraphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylarnino]phenyl-N'-(2-bromophenyl)urea
N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N'-(2-
broraophenyl)urea ; or
N-[2-(aminosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea.
15
25. A pharmaceutical composition comprising a compound according to any of Claims
20 to 24 and a pharmaceutically acceptable carrier or diluent.
26. A compound of the formula:
20
wherein
X is oxygen or sulfur;
X i is oxygen or sulfur;
25 Ri is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io
alkyl; Ci-ioalkyl; C2-10 alkenyl; Ci-ioalkoxy; halosubstituted Cmo alkoxy; azide;
S(0)tR4; hydroxy; hydroxyCi-4alkyl; aryl; aryl Ci_4 alkyl; aryloxy; aryl Ci-4
alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclicCi-4alkyl;
heteroarylC 1-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic
30 C2-10 alkenyl; NR4R5; C2-10 alkenyl C(0)NR4R5; C(0)NR4R5; C(O)NR4Rl0;
S(0)3H; S(0)3R8; Ci- 10 alkyl C(0)Ri 1; C2-10 alkenyl C(0)Ri 1; C2-10 alkenyl
C(0)ORi 1 ; C(0)Ri 1 ; C(0)OR 1 2; OC(O) R 1 1 ; NR4C(0)R 1 1 ; or two R ] moieties
together may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring;
t is 0, or an integer having a value of 1 or 2;
35 s is an integer having a value of 1 to 3;
AMENDED SHEET (ARTICLE 19)
WO 96/25157
-111-
BCT/US96/02260
R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci_4alkyl, optionally substituted heteroaryl,
optionally substituted heteroaryl C 1.4 alkyl, heterocyclic, heterocyclic Cj-4 alkyl, or
R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member
5 ring which may optionally comprise an additional heteroatom selected from O/N/S;
Y is independently selected from halogen; nitro; cyano; halosubstituted Ci-io alkyl; C\.\o
alkyl; C2-l0alkenyl; Ci-io alkoxy; halosubstituted C 1 . 1 0 alkoxy; azide; S(0) t R4;
hydroxy; hydroxy Ci^alkyl; aryl; aryl C1.4 alkyl; aryloxy; aryICj-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroarylC 1 .4 alkyloxy; heterocyclic, heterocyclic Ci-
10 4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-IO alkenyl;
NR4R5; C2-IO alkenyl C(0)NR 4 R 5 ; C(0)NR 4 R 5 ; C(O)NR4Rl0; S(0)3H; S(0)3R 8 ;
C 1 . 1 0 alkyl C(0)R 1 1 ; Ci- 1 0 alkenyl C(0)R 1 1; C2- 1 0 alkenyl C(0)OR 1 1 ; C(0)R 1 1 ;
C(0)ORi2; OC(O) Ri 1; NR4C(0)Ri 1; or two Y moieties together may form
0-(CH2)sO- or a 5 to 6 membered unsaturated ring;
15 n is an integer having a value of 1 to 2;
m is an integer having a value of 1 to 3;
R8 is hydrogen or C 1^4 alkyl;
RlO is C 1-10 alkyl C(0)2R8;
Rl 1 is hydrogen, C1-4 alkyl, optionally substituted aryl, optionally substituted aryl
20 C 1 -4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1 .
4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic Cj.
4alkyl;
Rl2 is hydrogen, C\. \q alkyl, optionally substituted aryl or optionally substituted arylalkyl;
provided that:
25 when n =1 than Y is substituted in the 2'- or 3'- position;
when n =2 than Y is di-substituted in the 2 - 3'- position;
further provided that
when X 1 is S, m=l, Ri is 4-ethyl, and n=l than Y is not 2-methoxy;
or a pharmaceutical^ acceptably salt thereof.
30
27. The compound according to Claim 26 wherein R\ is substituted in the 3-position,
the 4- position or di-substituted in the 3,4- position by an electron withdrawing moiety.
28. The compound according to Claim 26 or 27 wherein Y is mono-substituted in the 2 -
35 position or 3'- position, or is disubstituted in the 2' or 3' position of a monocyclic ring.
29. The compound according to Claim 26 or 27 wherein n amd m are each equal to 1 or
more.
AMENDED SHEET (ARTICLE 19)
WO 96/25157
-112-
PCT/US96/02260
26 to 2Q A P H ham h aCeUtiCaJ com P™"- comprising a compound according to any of CI
26 to 29 and a pharmaceutical^ acceptable carrier or diluent.
5 31.
A process for producing a cyano phenol derivative of the formula:
wherein Rl is as defined for Formuia (I) above, which method comprises
a) reacting a compound of the formula-
OH *
1 wherein X is halogen
SIS d — • — - • ca^uc amounl of
SO-C. a^xTZT rd ' ng 10 Cla,m 3 ' Wherem ttmPera,Ure * ^ 60 » —
AMENDED SHEET (ARTICLE 19)
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US96/02260
A. CLASSIFICATION OF SUBJECT MATTER
H»C(6) :A61K 31/17
US CL :514/585, 596, 597, 598
According to International Patent Classification (I PC) or to both national classification and IPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system followed by classification symbols)
U.S. : 514/585, 596. 597, 598
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data bate consulted during the international search (name of data base and, where practicable, search terms used)
Please See Extra Sheet.
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category*
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
X, A
X, A
US, A, 4,048,333 (GALABOV ET AL) 13 SEPTEMBER 1977,
see entire document.
Chemical Abstracts, Volume 122, No. 7, issued 13 February
1995, Olesen et al, "Preparation of arylurea and amide
derivatives and their use in the control of cell membrane
potassium channels" see page 1042, column 2, abstract no.
80891s, WO, A, 94/22807.
9, 20-24, 26-
29,
1-8. 11-13
1-9, 11-13, 26-
29,
20-24
|j Further documents are listed in the continuation of Box C | | See patent family annex.
E"
•L*
"O"
Special categories of cited document*:
document defining the general slate of the art which is not considered
fo be of particular relevance
earlier document published on or after the international filing date
t which may throw doubts on priority claim(s) or which is
cited to establiah the publication date of anoUier citation or other
i (as specified)
referring to an oral disclosure, use, exhibition or oilier
docsjsnesst publis he d prior to the international filing dulc but tutor Uuui
the priority date claimed
later document published after the international filing date or priority
date and not in conflict with the application but cited to understand die
principle or theory underlying the invention
document of particular relevance; the claimed invention cannot be
considered novel or cannot be considered to involve an inventive step
when the document is taken alone
document of particular relevance: the claimed invention cannot be
considered to involve an inventive step when the document is
combined with one or more other such documents, such combination
being obvious to a person skilled in the art
liovumtnl member of the nine patent family
Date of the actual completion of the international .search
16 APRIL 1996
Dale of inailin
Name and mailing address of the ISA/US
Commissioner of Patents and Trademarks
Box PCT
Washington. D.C 20231
Facaimile No. (703) 305-3230
Form PCT72S/V210 (aecond sheet)(July 1992)*
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US96/02260
Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
This international report has not been established in respect of certain claims under Article I7(2)(a) for the following reasons:
1. J~] Claims Nos.:
because they relate to subject matter not required to be searched by this Authority, namely:
2. I | Claims Nos.:
because they relate to parts of the international application that do not comply with the prescribed requirements to such
an extent that no meaningful international search can be carried out, specifically:
3. |^x] Claims Nos.: 10, 27(renumbered 25), and 30
because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
This International Searching Authority found multiple inventions in this international application, as follows:
Please See Extra Sheet.
1 • [* | As all required additional search fees were timely paid by the applicant, this international search report covers all searchable
claims.
2. | | As all searchable claims could be searched without effort justifying an additional Ice, this Authority did not invite payment
of any additional fee.
3. [ | As only some of the required additional search Ices were timely paid by the applicant, this international search report covers
only those claims for which fees were paid, specifically claims Nos.:
*• | x| No required additional search fees were timely paid by the applicant. Consequently, this international search report is
restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
1-9, 11-27 renumber to 25, 28 renumber to 26 and 27-29.
Remark on Protest j[_Jj The additional search fees were accompanied by the applicant's protest.
| 1 No protest accompanied the payment of additional search fees.
Form PCT/1S A/210 (continuation of first shcet(l))(July 1992)*
INTERNATIONAL SEARCH REPORT
International application No.
PCT/US96/02260
B. FIELDS SEARCHED
Electronic data bases consulted (Name of data base and when: practicable tenns used):
STN: REGISTRY (STRU CTU RE) , CA
search terms: chemokinc, inlerieukin, IL-8, psoriasis, dermatitis, asthma, arthritis, colitis, septicemia, stroke,
reperfusion, thrombosis, alzheimer's disease, graft vs. host, allograft rejection
BOX II. OBSERVATIONS WHERE UNITY OF INVENTION WAS LACKING
This ISA found multiple inventions as follows:
I. Claims 1-13, 20-24, 27(renumbered 25), 28(renumbcred 26), 27-30, drawn to methods and compounds thereof
D. Claims 14 and IS, drawn to compounds and a pharmaceutical composition
III. Claim 16, drawn to a method
IV. Claims 17 and IS, drawn to compounds and a pharmaceutical composition
V. Claim 19, drawn to a method
VI. Claims 31 and 32, drawn to a process for making compounds
The inventions listed as Groups l-VI do not relate to a single inventive concept under PCT Rule 13.1 because, under
PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons: There are
three different groups of compounds claimed with each yroup having basic structures considerably different than the
others. Although all of the compounds (except those in the last two claims) have a common urea core, the variance in
carbocyclic and heterocyclic rings of the core results in each group of compounds being distinct from the others. This
is further made evident by the fact that the skilled artisan would not expect that the compounds of the three groups
would have similar biological activity. Clearly, the three groups of compounds and pharmaceutical compositions, and
the corresponding groups of methods, do not have a common technical feature and therefore lack unity of invention.
Applicant should note that two sets of claims were numbered 27 and 28. Since it appears that the first set of claims
were intended to be numbered 25 and 26, all four claims have been examined for lack of unity.
Form PCT/ISA/210 (extra sheet)(July 1992)*
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